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The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intes-tine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signalingmolecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for main-taining systemic homeostasis. Tài liệu gồm 14 trang, giúp các bạn tham khảo, ôn tập và đạt kết quả cao. Mình bạn đọc đón xem!

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Tác giả:

Hân Hân

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Danh sách Quiz

Pharmacology & Therapeutics xxx (xxxx) xxx

Regulation of organic anion transporters: Role in physiology,

pathophysiology, and drug elimination

Jinghui Zhang, Haoxun Wang, Yunzhou Fan, Zhou Yu, Guofeng You

⁎

Department of Pharmaceutics, Rutgers, the State University of New Jersey, Piscataway, NJ, USA

A R T I C L E I N f О A B S T R A C T

Available online xxxx

The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intes-

tine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling

Keywords:

Drug transporter

Organic anion transporter

Drug disposition

Post-translational modi

cation

Regulation

Contents

molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for main-

taining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and

inter-individual variability of the therapeutic ef

cacy and the toxicity of many drugs, and to many pathophysio-

logical conditions. Consequently, the activity of these transporters must be highly regulated to carry out their

normal functions. This review will present an update on the recent advance in understanding the cellular and

molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modi

ca-

tion (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowl-

edge will provide signi

cant insights into the roles of these transporters in health and disease.

Introduction

...........................................................................................................................................................................................

OAT expression, structure, and function

...........................................................................................................................................

OATs and drug-drug interaction (DDI)

...............................................................................................................................................

OATs in kidney injury and diseases

...................................................................................................................................................

Genetic polymorphisms of OATs and clinical impact

......................................................................................................................

Roles of OATs in the handling of endogenous substances and their metabolites

.......................................................................

Regulations of OATs

..............................................................................................................................................................................

Conclusion

..............................................................................................................................................................................................

Acknowledgements

........................................................................................................................................................................................

Reference

.........................................................................................................................................................................................................

Introduction

Organic anion transporters (OATs), a subfamily of the solute carrier

22 (SLC22) transporters, are localized on the physiological barriers of

Abbreviations: OAT, organic anion transporter; TMD, transmembrane domain; DDI,

drug

–

drug interaction; Nedd4-1/Nedd4-2, neural precursor cell expressed developmen-

tally down-regulated 4-1/4-2; PTM, post-translational modi

cation; DUB,

deubiquitinating enzyme; Sgk, serum- and glucocorticoid-inducible kinase; PKA, protein

Kinase A; PKB, protein Kinase B; PKC, protein Kinase C; USP8, ubiquitin-speci

c protease

8; SENP, SUMO1/sentrin speci

c peptidase; IGF-1, Insulin-like growth factor 1.

Corresponding author at: Department of Pharmaceutics, Rutgers, The State University

of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.

E-mail address: gyou@pharmacy.rutgers.edu (G. You).

multiple tissues, such as kidney, liver, brain, placenta, retina, and olfac-

tory mucosa (He et al., 2014; S. K. Nigam et al., 2015). They are the key

players for the translocation of various substances into and out of cells,

such as signaling molecules, toxins, and a diverse array of important

clinical therapeutics, including antivirals, anti-cancer drugs, antibiotics,

anti-hypertensives, and anti-in

ammatories. (Ahn & Nigam, 2009; Cha

et al., 2000; Dantzler & Wright, 2003; He et al., 2014; Pritchard, 1990;

Srimaroeng, Perry, & Pritchard, 2008; Taki, Nakamura, Miglinas,

Enomoto, & Niwa, 2006; Terada & Inui, 2007; Vallon et al., 2008;

VanWert, Gionfriddo, & Sweet, 2010; You, 2002). Therefore, OATs are

not only critical for physiological and pathological processes in the

body, but also critical in absorption, distribution, metabolism, and

elimination

(ADME)

clinical

therapeutics,

thus

affecting

the

https://doi.org/10.1

016/j.pharmthera.20

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/pharmthera

20.107647 0163-

Elsevier Inc. All

rights reserved.

Fig. 1. Major drug transporters expressed in human renal proximal tubule cells. MRP: multidrug resistance-associated protein, OCT: organic cation transporter, OAT: organic anion

transporter, OATP: organic anion-transporting peptide, MATE: multidrug and toxin extrusion protein, PEPT: peptide transporter, BCRP: breast cancer resistance protein, MDR:

multidrug resistance mutation, URAT: urate transporter.

pharmacokinetics and pharmacodynamics of the drug pro

le. Among

the tissues involved in the ADME of clinical therapeutics, the kidney is

one of the vital organs responsible for drug elimination after its admin-

istration. Renal drug transporters are in charge of the transfer of the

drugs between blood and proximal tubule lumen. Among various

renal drug transporters, OATs, mainly interacting with organic anionic

molecules, are expressed at both the basolateral membrane and apical

membrane of the proximal tubule cells and are responsible for the ex-

cretion of numerous endogenous and exogenous substances. Because

of the importance of OATs in disposition of many important clinical

drugs and in various physio-pathological processes, numerous efforts

have been made to uncover molecular and cellular mechanisms that

contribute to the regulation of OATs. In this review, we discussed the re-

cent advance in understanding the regulation of OATs, highlighting the

regulation at the level of post-translational modi

cation and the regula-

tory network of the remote sensing and signaling.

OAT expression, structure, and function

The OAT family consists of a group of transmembrane proteins with

around 540-560 amino acids. The OATs have been identi

ed in the epi-

thelia barriers such as kidney, liver, brain, placenta, and intestine. These

OATs play signi

cant roles in modulating the movement of organic

anion molecules across cell membranes. One of the characteristics of

OATs is their wide range of substrate recognition including both physi-

ological/endogenous substrates and their metabolites and xenobiotic

molecules such as environmental toxins and therapeutic drugs, which

makes them important players in body homeostasis and pharmacolog-

ical responses (VanWert et al., 2010). Understanding the relationships

between the molecular features of OATs and their functions provided

signi

cant insights into their in

uences on clinical drug elimination, ef-

cacy, and toxicity. (Emami Riedmaier, Nies, Schaeffeler, & Schwab,

2012; Koepsell, 2013; S. K. Nigam et al., 2015; L. Wang & Sweet,

2013b; D. Xu, Wang, & You, 2016b).

Kidney is responsible for eliminating substances from the blood and

reabsorbing certain compounds back into the circulation. In this way it

keeps essential nutrients in the circulation while removing harmful me-

tabolites and therapeutic agents from the body (L. Wang & Sweet,

2013b). There are three major events in this process: glomerulus

ltra-

tion, tubule secretion, and reabsorption. Unlike the passive

ltration

processes occurring in kidney glomeruli, much of the active exchange

of compounds happen in the kidney proximal tubule, where a number

of important transporters are expressed (Fig. 1). Proximal tubule cells

polarize into apical membrane, which faces the urine, and basolateral

membrane, which faces the blood vessel. The OAT members are

expressed in renal proximal tubule, both on the basolateral and on the

apical membrane. They stand as important mediators in the active pro-

cess of renal elimination and reabsorption (Emami Riedmaier et al.,

2012; Motohashi et al., 2013).

In human, OAT1, OAT2, OAT3, OAT4, OAT10, and URAT1 have been

detected in kidney samples. It is worth to mention that in rodents cer-

tain Oats have different expression pro

les from those in human.

These comparisons could help to understand the differences of OAT

functions and regulations between rodent models and clinical studies.

(S. K. Nigam et al., 2015; L. Wang & Sweet, 2013b). OAT1, OAT2, and

OAT3 have been located on the basolateral membrane of the proximal

tubule cells in human kidney, which is the blood side of these cells

(Fig. 1). These three OATs facilitate the transfer of organic anions from

blood into the proximal tubule cells driven by a tertiary transporting

mechanism. Across basolateral membrane, the cells utilize the sodium

gradient generated by

-K

ATPase to indirectly drive the in

ux of

organic anions into the proximal tubule cells. OAT4 and URAT1 (another

member of OAT family) are expressed on the apical membrane or the

urine side of the proximal tubule cells (Fig. 1). OAT4 mediates

reabsorption of organic anions from urine back into the tubule cells.

OAT10, with higher expression in kidney proximal tubule and small in-

testine, has been proved to transport nicotine and uric acid. URAT1 is

mainly responsible for the reabsorption of urate via monocarboxylates

exchange. (S. K. Nigam et al., 2015; L. Wang & Sweet, 2013b).

Through computer modeling and site-directed mutagenesis studies,

it has been revealed that OAT family shares a similar structure feature

consisting of intracellular N- and C-termini, 12 α-helical transmem-

brane domains (TMDs), a large extracellular loop between TMD1/2,

and a central intracellular loop between TMD6/7 (Anzai, Kanai, &

Endou, 2006; F. Zhou & You, 2007; Zhu et al., 2015). Three highly con-

served regions are mainly responsible for protein functions: the large

extracellular domain between TMD1/2, the central intracellular loop be-

tween TMD6/7, and TMD9/10. These three regions work together to en-

sure substrate speci

city and proper transport activity of OATs

(Koepsell, 2013; Zhu et al., 2015). Furthermore, the large extracellular

domain between TMD1/2 contains multiple glycosylation sites, which

are important for OAT traf

cking to cell surface (F. Zhou et al., 2005).

The C-terminus and central intracellular loop between TMD6/7 contain

potential phosphorylation sites, which are involved in regulations of

transport function and expression (Zhu et al., 2015). OAT1 formed

homo-oligomers on plasma membrane when expressed in cell culture,

which were con

rmed via co-immunoprecipitation and gel

ltration

chromatography (Hong et al., 2005). TMD6 is important to homo-

oligomerization of OAT1 on plasma membrane, which plays a signi

cant role on transporter expression and activity (P. Duan, Li, & You,

2011). In addition, TMD12 has been shown to play a critical role in

OAT maturation and stability (Hong, Li, Zhou, Thomas, & You, 2010).

OATs and drug-drug interaction (DDI)

Clinically observed DDIs can be dated back to more than 50 years ago

with the co-administration of probenecid and penicillin. Probenecid, an

inhibitor for organic anion transport system, inhibited the renal clear-

ance of penicillin, consequently increased the ef

cacy of penicillin

(Gibaldi & Schwartz, 1968). With progress in molecular cloning and

characterization of individual OATs, molecular and cellular mechanisms

underlying OAT-mediated DDIs have been revealed. Due to the vast

range of substrate recognition of OATs, multiple therapeutic agents,

when taken together, may mutually affect each other

’

s pharmacokinetic

pro

les through interacting with the same transporters, either in a com-

petitive or non-competitive manner, which causes drug

–

drug interac-

tion (Huo & Liu, 2018; L. Wang & Sweet, 2013b). It would be

impractical to assess all the DDI possibility of approved drugs and new

drug candidates only in clinical studies. Thus, cell line-based in vitro

DDI assays are proven to be valuable research tools (Giacomini et al.,

2010; Huo & Liu, 2018). In recent years, the US Food and Drug Adminis-

tration (FDA) with International Transporter Consortium have issued

guidance for the assessment of transporter-mediated drug

–

drug inter-

actions during drug development process. Among the important drug

transporters, OAT1 and OAT3 were listed as potential targets for DDI

assessment (Giacomini et al., 2010; Hillgren et al., 2013).

Numerous in vitro OAT-mediated DDI studies of therapeutic drugs,

such as anti-tuberculosis drugs, anti-viral drugs, and anti-cancer

drugs, have been reported (Maeda et al., 2014; Parvez, Kaisar, Shin,

Jung, & Shin, 2016; Toh et al., 2016; L. Wang, Pan, & Sweet, 2013; L.

Wang & Sweet, 2013a). In a recent study, OAT4-expressing cells were

utilized to screen a panel of anti-cancer drugs. Epirubicin hydrochloride

and dabrafenib mesylate showed cis-inhibitory effect on OAT4 uptake

activity. Furthermore, it was discovered that dabrafenib mesylate

exerted competitive inhibition while inhibition by epirubicin hydro-

chloride was in a noncompetitive manner, and epirubicin hydrochloride

had a higher chance causing clinical DDI (C. Liu, Zhang, & You, 2019). In

a rat study both mizoribine and beza

brate were found to be Oat1 and

Oat3 substrates. The co-administration of mizoribine and beza

brate in-

creased the accumulation of beza

brate in the circulation, causing

enhanced toxicity and increased risk of developing rhabdomyolysis

(Feng et al., 2016). In addition to approved drugs, indoxyl sulfate, a ure-

mic toxin, was con

rmed as a substrate of OAT1, OAT3, and OAT4 in cul-

tured cells (Hsueh et al., 2016). In a rat study, the blood concentration of

indoxyl sulfate increased with lower renal clearance when adminis-

trated with quinapril, whose metabolite quinaprilat was also a substrate

of Oat3 (Fujita et al., 2012; Yuan et al., 2009). To connect in vitro studies

with in vivo research, Mathialagan, et al. applied transporter data ob-

tained from OAT-expressing human cells to quantitatively predict

in vivo renal elimination and total renal clearance. Their results con-

cluded that renal transport mediated by OAT3 played a predominant

role in renal elimination for a majority of drugs they tested

(Mathialagan et al., 2017).

Recognized as a powerful organic anion transport inhibitor, proben-

ecid was used with clinical therapies to prolong half-life of drugs there-

fore enhance therapeutic effects (L. Wang & Sweet, 2013b). In healthy

volunteers, probenecid inhibited the clearance of mesna, an OAT sub-

strate, increasing its protective effect against the toxicity of cyclophos-

phamide and cisplatin (Cutler et al., 2012). However, inhibition of

OATs works as a double-edged sword, which may cause higher system-

atic toxicity when exposing whole body to a drug for an extended time

(Takahara et al., 2013). In a clinical study of patients with non-small cell

lung cancer, hematologic toxicity caused by pemetrexed was ampli

when lansoprazole was co-administrated. Cell line-based study later

con

rmed that lansoprazole inhibited OAT3, thus decreased the renal

uptake and elimination of pemetrexed, and eventually increased hema-

tologic toxicity in patients (Ikemura et al., 2016). A clinical study found

that AK106

–

001616, a cytosolic phospholipase A2 inhibitor, inhibited

OAT1 and OAT3 and increased the area under curve of methotrexate

in rheumatoid arthritis patients (Kozaki et al., 2015). In cancer patients

who received methotrexate, a drug for arthritis and cancer, with proton

pump inhibitors, their plasma concentrations of methotrexate were sig-

cantly higher than those in patients taking methotrexate alone,

which was consistent with another cell-based study using cultured

cells expressing OAT1 and OAT3. It was found that proton pump

inhibitors like omeprazole signi

cantly decreased the uptake of metho-

trexate through inhibiting OAT1 and OAT3 (Chioukh et al., 2014;

Narumi et al., 2017). In summary, with expanding knowledge and

discoveries, OAT-mediated DDIs continue to play signi

cant roles in

the pharmacokinetic pro

les, ef

cacy, and toxicity of a wide range of

clinical therapeutic agents.

OATs in kidney injury and diseases

Clinical observations between kidney diseases and renal OATs are

often complex and intertwined. On one hand, kidney injury and dis-

eases could directly affect renal OAT expression, function, and localiza-

tion. On the other hand, direct damage on proximal tubule cells and

OATs could also change various renal functions, leading to kidney dis-

ease progression. Plentiful animal and clinical studies have revealed

possible correlations between them (Huo & Liu, 2018; Schwenk & Pai,

2016; L. Wang & Sweet, 2013b; D. Xu, Wang, & You, 2016b).

Acute kidney injury (AKI) is a common and complex condition

especially for patients in the intensive care units. The well-recognized

causes of AKI are drug/toxicant-induced renal toxicity and renal

ischemia/reperfusion (L. Wang & Sweet, 2013b). Renal ischemia/reper-

fusion often decreases Glomerular

ltration rate (GFR) and damages

tubular functions like secretion and reabsorption (Bischoff, Bucher,

Gekle, & Sauvant, 2014b). In ischemic rat kidneys, the mRNA and

protein expression levels of Oat1 and Oat3 were both reduced

(Bischoff et al., 2014b; Schneider et al., 2015). Anti-in

ammatory

drugs meclofenamate, quercetin, and resveratrol reduced indoxyl

sulfate accumulation during AKI and ameliorated the reduction of

Oat1 and Oat3 protein expression in ischemic AKI rats (Saigo et al.,

2014; Saito et al., 2014). Prostaglandin E2 decreased the mRNA levels

of Oat1 and Oat3 through E prostanoid receptor type 4 in rats with

ischemic-induced AKI (Bischoff, Bucher, Gekle, & Sauvant, 2014a;

Preising, Schneider, Bucher, Gekle, & Sauvant, 2015). A wide range of

clinical therapeutics could cause renal toxicity and induce AKI, such as

aminoglycosides antibiotics and angiotensin-converting-enzyme inhib-

itors (Pannu & Nadim, 2008). Previous research revealed that gentami-

cin can cause necrosis of proximal tubule cells, which would inhibit

protein synthesis in kidney and induce AKI. Furthermore, gentamicin

was able to increase the levels of superoxide anion and hydrogen perox-

ide in renal cortical cells, which would also contribute to renal toxicity

(Baliga, Ueda, Walker, & Shah, 1999). In a rat model of gentamicin-

induced AKI, both plasma creatinine and blood urea nitrogen levels

were increased, indicating reduced renal function and toxicity. In this

AKI model, both the mRNA and protein expressions of Oat1 and Oat3

were signi

cantly decreased. It was possible that gentamicin-caused

toxicity down-regulated kidney Oat1 and Oat3 expression, which con-

tributed to the reduced renal function and accumulated endogenous

substances (X. Guo et al., 2013). Resveratrol, an anti-in

ammatory and

antioxidant agent, reduced methotrexate-induced renal toxicity in rats

via decreasing Oat-mediated kidney elimination of methotrexate. This

reduced toxicity was mainly due to direct inhibition by resveratrol on

Oat1 and Oat3 (Jia et al., 2016).

In patients with chronic kidney failure (CKF), the glomerular

ltra-

tion rate and renal clearance decline gradually and continuously,

which would cause endogenous metabolites, uremic toxins, and thera-

peutic agents to accumulate in the circulation and often lead to renal

failure (Naud et al., 2011). In the process, uremic toxins exert effects

on OATs in two aspects. On one hand, uremic toxins could regulate

OAT expression. In a rat model of adenine-induced CKF, the mRNA

and protein expression levels of Oat1 and Oat3 were signi

cantly re-

duced (Komazawa et al., 2013). In a CKF rat model by 5/6 nephrectomy,

Oat1, Oat2, and Oat3 mRNA and protein expression levels were reduced.

Interestingly, incubating human proximal tubule cells with sera from

CKF rats caused a similar decreasing effect on human OATs (Naud

et al., 2011). The authors hypothesized that the decreasing effects on

OAT/Oat were possibly due to accumulated metabolites and uremic

toxins in the sera of CKF rats, although regulatory mechanisms were

not clearly revealed. In support, p-cresyl sulfate, a uremic toxin, reduced

Oat1 expression in a separate animal study. Oat1 protein expression

was decreased by 40% after p-cresyl sulfate administration by oral ga-

vage in CKF rats (Jansen et al., 2019).

In addition to the regulation on OAT expression, accumulated me-

tabolites and uremic toxins could also inhibit OAT transport activity

and cause OAT-mediated drug-drug interactions (DDI) (Huo & Liu,

2018). Accumulated indoxyl sulfate (IS) and hippuric acid decreased

renal clearance of morinidazole metabolites, substrates of Oat1 and

Oat3, through Oat-mediated DDIs in CKF rats. Thus the plasma concen-

trations of morinidazole metabolites were signi

cantly elevated (Kong

et al., 2017; Zhong et al., 2014). In CKF rats, green tea metabolites fur-

ther reduced kidney clearance and increased the plasma levels of IS

and p-cresyl sulfate by inhibiting the functions of Oat1 and Oat3 (Peng

et al., 2015). The complex relationship between uremic toxins and

OATs has also been reported in Oat1 and Oat3 knockout mice (A. K.

Nigam et al., 2020; W. Wu, Bush, & Nigam, 2017). In Oat1 knockout

mice, the levels of IS, kynurenine, and xanthurenic acid were increased

in the plasma, and these toxins could inhibit Oat1 function in vitro

(Wikoff, Nagle, Kouznetsova, Tsigelny, & Nigam, 2011). Indoleacetate

and p-cresyl sulfate were signi

cantly increased in the plasma of Oat3

knockout mice, and their interactions with Oat3 were also con

rmed

by in vitro data (W. Wu et al., 2017). In conclusion, the interaction be-

tween uremic toxins and renal OATs is complicated under CKF condi-

tions. The accumulated metabolites and uremic toxins due to

decreased expression and function of OATs in CKF would in turn further

reduce OAT function, which forms a positive feedback loop between

uremic toxins and OATs.

A wide range of other pathological conditions were also revealed to

affect functions and expressions of renal OATs in animal studies. The

expression and function of Oats under diabetic conditions have been

studied in various animal models. One animal study showed that the ac-

tivity and protein level of Oat3 were decreased in streptozotocin-

induced diabetic rats, which could be restored by insulin treatment

(Phatchawan, Chutima, Varanuj, & Anusorn, 2014). In another study

using Ins2Akita mouse, a model for diabetes, the mRNA and protein ex-

pression levels of Oat1, Oat2, and Oat3 were all reduced (C. Xu et al.,

2015). Furthermore, the mRNA level of Oat2 were decreased in both

Ob/Ob obese mice and Db/Db diabetic mice (Cheng et al., 2008). In

obese rats with high fat diet (HF), it was reported that Oat3 transport

function and protein expression were decreased. Atorvastatin or

vildagliptin treatment in HF rats partially reversed the impaired renal

Oat3 function (Pengrattanachot et al., 2020). In addition to diabetes,

cholestasis, a liver disease, in which the

ow of bile from liver is reduced

or obstructed, was reported to affect renal Oats in animal models.

Administration of alpha-naphthyl isothiocyanate (ANIT) to induce bili-

ary obstruction in rats resulted in reduced protein expression of Oat1

and Oat3 (T. Liu et al., 2012). In rats with bile duct ligation (BDL),

protein expression of Oat1 was decreased while Oat3 expression was

increased (Brandoni, Anzai, Kanai, Endou, & Torres, 2006). The method

of BDL-induced biliary obstruction animal model is different from that

of ANIT-induced intrahepatic cholestasis model, which possibly contrib-

utes to the difference in the variation of OAT3 expression in both

reports. In a rat model of bilateral ureteral obstruction, a disease that

blocks the

ow of urine from kidney to bladder, the transport activity

and protein expression levels of Oat1 and Oat3 in the kidney were

reduced (Villar, Brandoni, & Torres, 2008).

In addition to animal models, OAT expression was investigated in

multiple clinical studies. In patients with metastatic colorectal cancer,

higher OAT2 expression was detected in tumor tissues after 5-

uorouracil/leucovorin/oxaliplatin (FOLFOX) treatment. And higher

OAT2 level was signi

cantly correlated with good objective tumor re-

sponse which could serve as an independent predictor of good

FOLFOX treatment outcome, possibly due to the roles of OAT2 in uptake

of the FOLFOX drugs (Tashiro et al., 2014). In hepatocellular carcinoma

(HCC) patients who received curative local ablation therapy, those

with reduced OAT2 expression had signi

cantly higher rates of multifo-

cal recurrence than those with normal OAT2 expression. In addition, the

decreased level of OAT2 was signi

cantly correlated with future devel-

opment of HCC in chronic hepatitis C virus infected patients (Yasui et al.,

2014). The mRNA level of OAT1 was signi

cantly lower in kidney biopsy

specimens from patients with renal diseases compared to normal kid-

ney cortex tissues, while the levels of OAT2/4 mRNA seemed to increase

slightly (Sakurai et al., 2004).

In recent years, adjusting drug dosage became necessary in patients

with renal injury and diseases. The changes in GFR as well as renal OAT

expression and functions should be taken into consideration to achieve

an effective therapy. Thus, further studies of mechanistic connections

between OATs and various diseases are required to improve therapeutic

cacy and reduce possible toxicity in patients with altered renal

functions.

Genetic polymorphisms of OATs and clinical impact

In recent years, correlation analysis between OATs polymorphisms

and diseases in clinical studies were performed to further validate the

physiological function of OATs. A human study including normal sub-

jects and patients with chronic kidney disease (CKD) demonstrated

that patients with CKD had a higher frequency of the

−

475 single nucle-

otide polymorphisms (SNP) in the 5

’

regulatory region in OAT1 than

normal subjects. Moreover,

−

475 SNP in OAT1 with T to G transversion

reduced the binding of hepatoma-derived growth factor (HDGF, a

known transcription repressor), and HDGF can down-regulate OAT1

protein expression, suggesting an increase of OAT1 expression and

renal uptake of toxins, and nephrotoxicity with the

−

475 SNP (Sun

et al., 2018). In HEK293 cells, the OAT3-Ile305Phe variant had a reduced

maximum transport activity for cefotaxime, a substrate of OAT3 without

affecting the Michaelis-Menten constant value of OAT3, and a signi

cantly decreased surface expression of OAT3. As OAT3-Ile305Phe vari-

ant accounts for about 3.5% allele frequency in Asians, a clinical study

showed that OAT3-Ile305Phe variant signi

cantly suppressed the

renal clearance of cefotaxime, in healthy volunteers (Yee et al., 2013).

Besides, a SNP (Position at chromosome11: 64088038, A/G) of OAT4

was associated with renal underexcretion type gout by analysis of

OAT4 gene in gout patients and healthy volunteers, suggesting that

OAT4 expressed at apical membrane of renal proximal tubule cells con-

tributed to urate transport in humans (Kolz et al., 2009; Sakiyama et al.,

2014). Cho et al found that

ve new SNPs in the human URAT1 gene

were signi

cantly associated with uric acid concentration in blood by

analyzing subjects with normal uric acid level and subjects with hyper-

uricemia (Cho, Kim, Chung, & Jee, 2015). Among the

ve SNPs,

rs75786299 had the highest association with hyperuricemia, followed

by rs7929627 and rs3825017, while rs11602903 and rs121907892

were negatively correlated with hyperuricemia. OAT1 and OAT3 at the

basolateral membrane of the kidney proximal tubule cells may affect se-

cretion of uric acid rather than reabsorption like URAT1 at the apical

membrane, which was con

rmed in Oat1 knock-out (Oat1KO) and

Oat3 knock-out (Oat1KO) mice (Eraly et al., 2008). It is interesting

that there are few SNPs of OATs in uric acid-related human diseases

(such as hyperuricemia or hypouricemia) and other types of diseases

according to genome-wide association studies, which is possibly due

to the overall low-frequency genetic variants of OATs compared with

other transporters with high polymorphisms (Lipkowitz, 2012; Lozano

et al., 2018). One study found that a SNP (rs3793961) of OAT3 had asso-

ciation with lower serum uric acid levels among men with CKD

(Bhatnagar et al., 2016). Besides, intestinal secretion of uric acid by

ATP-binding cassette transporter G2 (ABCG2), a key luminal intestinal

secretory urate transporter may play a complementary role for renal ex-

cretion (Ichida et al., 2012). In the 5/6 nephrectomy rats with CKD, the

serum uric acid did not increase despite the urine uric acid excretion

in the kidney signi

cantly decreased; under such condition, overexpres-

sion of Abcg2 in intestine was observed, suggesting that Abcg2 in intes-

tine possibly rescued uric acid excretion in renal failure (Yano, Tamura,

Kobayashi, Tanemoto, & Uchida, 2014). Consistent with the rat model of

renal failure, Bhatnagar et al found that there was a signi

cant associa-

tion between serum uric acid and a SNP (rs4148157) on ABCG2 in intes-

tine in patients of European with CKD, further supporting that

intestinal-expressed ABCG2 remotely compensates to maintain uric

acid homeostasis in human with renal decline (Bhatnagar et al., 2016).

These clinical studies showed that genetic variants in drug transporters

can cause individual differences in drug effectiveness, drug toxicity, and

some diseases.

Roles of OATs in the handling of endogenous substances and their

metabolites

A variety of endogenous substances and their metabolites are elimi-

nated by renal OATs to avoid the systemic toxicity, and to maintain the

body

’

s homeostasis. Using Oat1 knock-out (Oat1KO) and Oat3 knock-

out (Oat1KO) mice permits to investigate the physiological role of

OAT1 and OAT3 without the interference from other functionally redun-

dant transporters, (Bush, Wu, Lun, & Nigam, 2017; Eraly et al., 2006).

Nigam

’

s group showed that the levels of more than 100 metabolites in

the plasma were altered which were involved in key metabolic path-

ways such as in vivo metabolism of gut microbiome products,

avo-

noids, bile acids, nutrients, amino acids, and lipids (Bush et al., 2017;

Eraly et al., 2006; A. K. Nigam et al., 2020; S. K. Nigam, 2018;

Rosenthal, Bush, & Nigam, 2019). Among those metabolites, many of

them are endogenous substrates of OATs, such as bile acids (cholic

acid and taurocholic acid) are substrates of OAT3, and Indoxyl sulfate

is substrate of OAT1 and OAT3 (Chen, Terada, Ogasawara, Katsura, &

Inui, 2008; Lin et al., 2018). Whether other metabolites are endogenous

substrates of OATs needs further to be validated. Besides, many metab-

olites are active signaling molecules, which will be discussed in detail in

section of

“

Remote Sensing and Signaling Hypothesis of OATs

”

. There-

fore, the abnormity of OATs under certain kidney diseases may impact

the handling of these endogenous substances and their metabolites.

Regulations of OATs

Given the crucial roles of OATs in physiological and pathological pro-

cesses and in determining the therapeutical ef

cacy and toxicity of

many clinical drugs, elucidating the cellular and molecular mechanisms

underlying OAT regulation is of great signi

cance. The regulations of

OATs can take place at multiple levels, such as at the levels of transcrip-

tion, post-transcription, translation, and post-translation, and numer-

ous signaling pathways are involved in these regulations.

Several transcription factors have been identi

ed to be involved in

the regulations of OATs. For example, in hepatocyte nuclear factor 1α

(HNF1α)-null mice, the levels of renal Oat1, Oat3, and Urat1 mRNA

were markedly reduced as compared to those in wild-type mice, and

HNF1α overexpression enhanced OAT1, OAT3, and URAT1 promoter ac-

tivity in vitro (Kikuchi et al., 2006; Kikuchi et al., 2007; Maher et al.,

2006; Saji et al., 2008). In ex vivo experiments with kidney organ cul-

ture, HNF4α antagonist attenuated the expression of Oat1 and Oat3

mRNA (Martovetsky, Tee, & Nigam, 2013). In addition, HNF4α

transactivated OAT1 promoter through DR-2 and IR-8 elements

in vitro (Ogasawara, Terada, Asaka, Katsura, & Inui, 2007). Furthermore,

B-cell CLL/lymphoma 6 (BCL6) increased OAT1 promotor activity de-

pendent on HNF1α element and HNF1α protein in vitro (Wegner,

Burckhardt, & Henjakovic, 2014). Besides, cAMP responsive element

binding protein 1 (CREB1) and activating transcription factor 1

(ATF1), and the corresponding DNA binding sequence motifs on OATs

were also involved in the regulation of OATs (Ogasawara, Terada,

Asaka, Katsura, & Inui, 2006). Several great review articles have already

covered the regulations of OATs at the levels of transcription, post-

transcription, and translation (Burckhardt, 2012; S. K. Nigam et al.,

2015; Terada & Inui, 2007; L. Wang & Sweet, 2013b). Therefore, we

will place our focus on the post-translational modi

cations of OATs in

the following discussion.

Post-translational modi

cations (PTMs), the alternations on the

amino acids of the target protein after its synthesis, refer to a process

of the covalent attachment of various functional group(s) to the

amino acid side chain, terminal amino, or carboxyl group of the target

protein (G. Duan & Walther, 2015; Spoel, 2018). Most of the PTMs are

dynamic and reversible processes which can be catalyzed by speci

c en-

zymes to promote or demote the modi

cation. These modi

cations in-

uence the expression, cellular localization, stability, structure, activity,

or substrate speci

city of the target proteins. PTMs provide complexity

to the proteome for diverse functions of the proteins. Various PTMs can

modify different parts of the target proteins individually or simulta-

neously. As a result, the functional diversities of the target proteins

much exceed their molecular diversities. Various PTMs of OATs have

been described in details in our previous review articles (P. Duan &

You, 2010; D. Xu, Wang, & You, 2016b; D. Xu & You, 2017). In this re-

view article, we will update the recent progress in uncovering the

new PTMs of OATs, the relationship among these PTMs, and the regula-

tory network on OATs through remote sensing and signaling.

7.1.

Regulation of OATs by direct phosphorylation

Phosphorylation process is a crucial PTM which adds negative

charged phosphoryl group(s) to the target protein catalyzed by protein

kinases, and the addition happens to a serine, threonine, or tyrosine res-

idue (Czuba, Hillgren, & Swaan, 2018). Phosphorylation is an important

regulatory mechanism for various membrane proteins including recep-

tors, channels, and transporters through a direct or indirect manner, and

Fig. 2. Phosphorylation of Ubiquitin ligase Nedd4-2 mediates the regulation of OAT transport activity by various kinases. U: ubiquitin, P: Phosphoryl group, S: Serine, T: Threonine, PKC:

Protein kinase C, Sgk1/2: Serum- and glucocorticoid-inducible kinase 1/2, Nedd4-2: Neural precursor cell expressed developmentally down-regulated 4-2.

induces the change in protein conformation, protein activity, cellular

localization of protein, protein stability, or protein-protein interaction.

Many membrane proteins are the substrates of protein kinase-

induced direct phosphorylation (Aromolaran, Chahine, & Boutjdir,

2018; Mayati et al., 2017). And many protein kinases have been re-

ported to phosphorylate various transporters. (Cetinkaya et al., 2003;

Foster & Vaughan, 2017). It is recently demonstrated that Protein Kinase

A (PKA) activation by Bt2-cAMP induced a signi

cant increase in OAT3

phosphorylation, which was correlated with an enhanced OAT3 trans-

port activity in cultured cells. Moreover, Insulin-like growth factor 1

(IGF-1), an upstream hormone of PKA signaling, increased OAT3 phos-

phorylation, and the stimulatory effect was abrogated by H89 (a selec-

tive PKA inhibitor). IGF-1-stimulated OAT3 phosphorylation was also

correlated with enhanced OAT3 transport activity and protein expres-

sion, and the up-regulation effect was abrogated by PKA inhibitor H89.

Therefore, PKA activation by Bt2-cAMP and IGF-1 up-regulated OAT3

expression and transport activity possibly by directly phosphorylating

OAT3 in COS-7 cells (J. Zhang, Yu, & You, 2020).

Dephosphorylation, countering phosphorylation, refers to a process

which removes phosphoryl group(s) from the target proteins, catalyzed

by phosphatases. Phosphorylation and dephosphorylation form an op-

posing regulatory network, thus affecting a variety of cellular processes

in health and disease (Ardito, Giuliani, Perrone, Troiano, & Lo Muzio,

2017; Vitrac, Mallampalli, & Dowhan, 2019). Phosphatase inhibitor

okadaic acid inhibited Oat1-mediated transport of para-aminohippurate

(PAH) in cultured cells, which was correlated with an increased phos-

phorylation of Oat1 (You, Kuze, Kohanski, Amsler, & Henderson, 2000).

7.2.

Regulation of OATs by indirect phosphorylation

Other than directly phosphorylating OATs, protein kinases could also

regulate OATs through phosphorylating OAT-interacting proteins. For

example, Nedd4-2, a ubiquitin ligase, is an OAT-interacting partner.

Ubiquitination of OATs, catalyzed by Nedd4-2, led to the internalization

of OATs from cell surface to intracellular endosomes and subsequent

degradation. Several protein kinases, hormones, and chemicals excreted

their regulation on OATs through phosphorylating Nedd4-2 at different

sites, which either weakened or strengthened the protein-protein inter-

action between OATs and Nedd4-2, and led to either stimulating or

inhibiting OAT activity (H. Wang, Liu, & You, 2018; H. Wang, Xu, Toh,

Pao, & You, 2016; H. Wang & You, 2017; H. Wang, Zhang, & You,

2019b; J. Zhang, Liu, & You, 2018).

Our published and unpublished results indicated PKC activation de-

creased OAT expression and transport activity through Nedd4-2 phos-

phorylation instead of directly phosphorylating OAT itself in cultured

cells (D. Xu, Wang, & You, 2016a; D. Xu, Wang, Zhang, & You, 2016; D.

Xu et al., 2017; You et al., 2000; Q. Zhang, Li, Patterson, & You, 2013).

Wolff et al further con

rmed such observation by site mutagenesis

assay: mutagenesis of

ve canonical PKC phosphorylation sites individ-

ually and in combination resulted in mutants that were insensitive to-

ward speci

c PKC activator dioctanoylglycerol in cultured cells (Wolff

et al., 2003). The short-term PKC/Nedd4-2 activation increased OAT

ubiquitination, leading to an accelerated endocytosis of OATs and a re-

duction of its cell surface expression and transport activity in cultured

cells. In addition, the prolonged PKC/Nedd4-2 activation resulted in

the endocytosed OAT to target to proteolytic system for degradation

(Fig. 2). (D. Xu, Wang, & You, 2016a; D. Xu, Wang, Zhang, & You,

2016; D. Xu et al., 2017). Angiotensin II, an endogenous hormone,

inhibited OAT1 and OAT3 transport activity through the activation of

PKC/Nedd4-2 pathway (P. Duan, Li, & You, 2010; S. Li, Duan, & You,

2009). Nedd4-2 phosphorylation happens not only on serine/threonine

residues, but also on tyrosine residues. AG490, a speci

c inhibitor of the

Janus tyrosine kinase 2 (JAK2), reduced OAT3 cell surface expression

and transport activity in cultured cells. The reduced transport activity

resulted from an enhanced OAT3 ubiquitination, following a reduced

Nedd4-2 tyrosine phosphorylation and an enhanced interaction be-

tween OAT3 and Nedd4-2. The inhibition effect of AG490 on OAT3

was abrogated by knocking down the endogenous Nedd4-2 using

Nedd4-2-speci

c siRNA (J. Zhang et al., 2018).

Some modulators of OATs reduce OAT transport activity through

Nedd4-2 phosphorylation, whereas others enhance OAT function

through phosphorylating Nedd4-2 at different sites. Overexpression of

serum and glucocorticoid-regulated kinase 1 (Sgk1) stimulated OAT3

transport activity in cultured cells. It was shown that Sgk1 phosphory-

lated Nedd4-2 on Ser327, which weakened the interaction between

OAT3 and Nedd4-2, and therefore decreased OAT3 ubiquitination

(Fig. 2) (H. Wang & You, 2017). Furthermore, Dexamethasone, an up-

stream hormone of Sgk1, stimulated OAT3 expression and transport

Fig. 3. Regulation of OATs by Ubiquitination, deubiquiting enzyme USP8, and proteasome inhibitors. U: ubiquitin, USP8: ubiquitin-speci

c proteases 8, Nedd4-1/Nedd4-2: Neural precursor

cell expressed developmentally down-regulated 4-1/4-2.

activity through Nedd4-2 phosphorylation in cultured cells (H. Wang

et al., 2018). Overexpression of Sgk2, an isoform of Sgk1, enhanced the

surface expression, total protein expression, and transporter activity

of OAT1 and OAT4 through impairing the binding between OATs and

Nedd4-2 and decreasing OAT ubiquitination in cultured cells (Fig. 2).

overexpression of Nedd4-2/C821A, a ligase-dead mutant of Nedd4-2,

or Nedd4-2 knockdown by Nedd4-2-speci

c siRNA abrogated the

stimulatory effect of Sgk2 on OATs, indicating Sgk2 regulated OATs

possibly through Nedd4-2 phosphorylation (H. Wang et al., 2016; D.

Xu, Huang, Toh, & You, 2016). Insulin, an endogenous hormone, in-

creased OAT4 transport activity resulting from an increased OAT4

cell surface. Furthermore, insulin up-regulated OAT4 through phos-

phorylating Nedd4-2 on Ser327, leading to the impaired association

between OAT4 and Nedd4-2. The up-regulation effect was abrogated

by knocking down the endogenous Nedd4-2 by Nedd4-2-speci

siRNA (H. Wang et al., 2019b). In summary, the dynamic phosphoryla-

tion of Nedd4-2, a central switch, at different sites exerts opposite reg-

ulations of OATs through different modulators, followed by distinct

conformational changes of Nedd4-2 and distinct associations between

Nedd4-2 and OATs, which leads to the change in OAT transport activ-

ity and expression.

7.3.

Regulation of OATs by ubiquitin-proteasome system

Ubiquitin, an 8.6 kDa protein, consists of 76 amino acids. The addi-

tion of ubiquitin to the lysine residue(s) of a substrate protein is called

ubiquitination, and ubiquitination could occur in different types of con-

jugation including monoubiquitination (conjugation of one single ubiq-

uitin to one single lysine on the substrate), multi-ubiquitination

(conjugation of several monoubiquitin molecules to multiple lysine res-

idues on the substrate), and polyubiquitination. Ubiquitin itself has

seven lysine residues and an N-terminal methionine residue including

K6, K11, K27, K29, K33, K48, K63, and M1, and a polyubiquitin chain is

formed between a glycine residue of one ubiquitin molecule and a ly-

sine residue or N-terminus of another ubiquitin molecule. The addition

of a polyubiquitin chain to a single lysine residue of the target protein is

called polyubiquitination (Komander & Rape, 2012; Pickart & Eddins,

2004). Ubiquitination regulates the target proteins by affecting their

activity, stability, cellular location, and their interactions with other

proteins.

The ubiquitin-proteasome system (UPS) is a major protein degrada-

tion system. Ubiquitination occurs in a sequence of three enzymatic

steps and ubiquitinated proteins are targeted to the 26S proteasome

for degradation (Bence, Sampat, & Kopito, 2001; Gong, Radulovic,

Figueiredo-Pereira, & Cardozo, 2016; Schwartz & Ciechanover, 2009).

The UPS has been reported to be involved in modulating OATs via alter-

ing cellular location and protein stability (Fig. 3).

7.3.1.

Regulation of OATs by ubiquitination and deubiquitination

Ubiquitination is a PTM that conjugates ubiquitin molecules to target

proteins, catalyzed by ubiquitination enzymes, including ubiquitin-

activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiq-

uitin ligase (E3). Nedd4-1 and Nedd4-2, the two E3 ubiquitin ligases,

have been identi

ed as important regulators for OATs (Fig. 3). Phorbol

12-Myristate 13-Acetate (PMA), a PKC activator, inhibited OAT trans-

port activity and expression in cultured cells. Such inhibition resulted

from an increased OAT ubiquitination, following PKC-promoted interac-

tion between OATs and Nedd4-2, which led to an accelerated internali-

zation of OATs from cell surface to early endosomes and subsequent

degradation (S. Li, Zhang, & You, 2013; D. Xu, Wang, & You, 2016a; Q.

Zhang, Suh, Pan, & You, 2012). Overexpression of Nedd4-1 or Nedd4-2

decreased the OAT1 protein expression and transport activity following

the enhanced OAT1 ubiquitination in cultured cells. Knocking down

endogenous Nedd4-2 with Nedd4-2-speci

c siRNA or overexpression

of Nedd4-2/C821A, a ligase-dead mutant of Nedd4-2, abrogated the

PKC-induced change in OAT1 ubiquitination, expression, and transport

activity in cultured cells. And PKC-dependent changes in OAT1 ubiquiti-

nation, expression, and transport activity were not affected by knocking

down endogenous Nedd4-1 or overexpression of Nedd4-1/C867S, a

ligase-dead mutant of Nedd4-1, in cultured cells (D. Xu, Wang, Zhang,

& You, 2016). In summary, ubiquitin conjugation to OATs, catalyzed

by Nedd4-1 or Nedd4-2, triggers the internalization of OATs from

plasma membrane to intracellular endosomes and subsequent degrada-

tion in proteolytic systems. As a result, the amount of OATs at the cell

surface is reduced, and OAT transport activity is subsequently

decreased. Nedd4-1 is mainly involved in the constitutive OAT

ubiquitination, whereas Nedd4-2 is largely involved in PKC-regulated

OAT ubiquitination.

Countering the ubiquitination is a process called deubiquitination

that removes ubiquitin molecules from the target proteins by

deubiquitinating enzymes (DUBs) (Amerik & Hochstrasser, 2004;

Komander, Clague, & Urbe, 2009). Ubiquitination and deubiquitination

form an opposing network and are related to a variety of physiological

and pathological processes (Cai, Culley, Zhao, & Zhao, 2018; Lee et al.,

2006; Y. Wu et al., 2018; Zheng et al., 2016).

To date, approximately 100 human DUBs has been found, and DUBs

can be classi

ed into six families including the ubiquitin-speci

c prote-

ases (USPs), the ubiquitin C-terminal hydrolases (UCHs), the Josephin

family, the ovarian tumor proteases (OTUs), Zn-dependent JAB1/MPN/

MOV34 metalloprotease DUBs (JAMMs), and the motif interacting

with ubiquitin (MIU)-containing novel DUB family (MINDYs). (Abdul

Rehman et al., 2016; Clague et al., 2013). A variety of membrane pro-

teins, such as channels, receptors, and transporters, are regulated

through deubiquitination process by DUBs (Butterworth et al., 2007;

Mines, Goodwin, Limbird, Cui, & Fan, 2009; L. Zhang et al., 2012; R.

Zhou et al., 2013).

The investigations on the regulation of OATs by DUBs demonstrated

that overexpression of USP8 decreased OAT1 ubiquitination, leading to

an increased OAT1 expression at the cell surface and an increased

OAT1 transporter activity in cultured cells (Fig. 3). No signi

cant differ-

ence in OAT1 expression and transport activity was observed in cells

transfected with an inactive mutant of USP8 as compared to those in

control cells. Furthermore, knocking down the endogenous USP8 in

COS-7 cells by USP8-speci

c siRNA led to an increase in OAT1

ubiquitination which correlated with a reduced OAT1 transport activity

(J. Zhang, Liu, & You, 2017).

7.3.2.

Regulation of OAT transport activity by proteasome inhibitors

The ubiquitin-proteasome system is the major proteolytic machin-

ery that degrades the majority of ubiquitinated intracellular proteins

and certain ubiquitinated membrane proteins in eukaryotic cells

(Alam, Farasyn, Crowe, Ding, & Yue, 2017; Jandial et al., 2009; Ogura

et al., 2011). Cancer cells have enhanced nuclear factor kappa B

(NF-kB) activity and are dependent on this signaling pathway for cell

survival and proliferation. Proteasome inhibition can down-regulate

NF-kB-dependent gene expression and lead to an arrest of tumor

growth. Besides, proteasome inhibition can stabilize tumor suppressor

proteins and repress cell cycle progression. As many cancer cells are

highly sensitive compared with normal cells for proteasome inhibition,

therefore proteasome has become an important drug target for cancer

therapy (Lenos & Vermeulen, 2016; Thibaudeau & Smith, 2019). The

26S proteasome is comprised of a proteolytic 20S core particle (20S pro-

teasome) and one or two capped 19S regulatory particles for recogniz-

ing the ubiquitinated proteins (Voges, Zwickl, & Baumeister, 1999).

Bortezomib, car

lzomib, and ixazomib, approved by FDA for the treat-

ment of patients with multiple myeloma, are reversible or irreversible

20S proteasome inhibitors with suppression of chymotrypsin-like activ-

ity. The pharmacodynamic study showed car

lzomib signi

cantly

inhibited the 20S proteasome activity in the kidney of Sprague-

Dawley rats (FDA, 2012). As ubiquitination is one essential post-

translational modi

cation which mediates the regulation of OATs, the

alteration of proteasome activity induced by proteasome inhibitors

can also potentially affect the transporter function.

At clinically therapeutic concentrations, incubation of OAT1-

expressing HEK293 with bortezomib or car

lzomib led to a signi

cant

accumulation of ubiquitinated OAT1, suggesting that ubiquitinated

OAT1 degraded through proteasomes (Fan, Wang, & You, 2018; Fan &

You, 2020). Bortezomib and car

lzomib signi

cantly stimulated trans-

port activity, and there was a positive correlation between the degree

of proteasomal inhibition by bortezomib and augmentation of OAT1

transporter activity. Bortezomib- and car

lzomib-induced increase in

OAT1 surface expression and transport activity were mainly attributed

to a decrease of OAT1 degradation rate (Fig. 3). Therefore, proteasome

inhibitors can provide a novel tool to reverse the ubiquitination-

induced downregulation of OATs expression and transport activity, in-

dicating their potential in

uence on the renal OATs-mediated drug dis-

position and drug-drug interactions. Besides, other proteasome

inhibitors are currently in clinical trials, and their in

uences on the kid-

ney OATs could be attentioned.

7.4.

Regulation of OATs by SUMOylation and deSUMOylation

SUMOylation and deSUMOylation, a pair of opposing and dynamic

PTMs, refer to the process, which adds SUMO to or removes SUMO

from lysine residue of the target protein, catalyzed by speci

c enzymes.

SUMOylation and deSUMOylation create an on and off switch which is

essential for biological regulations and are involved in various cellular

processes in health and disease (Flotho & Melchior, 2013; C. Guo &

Henley, 2014; Zhao, 2007).

7.4.1.

Regulation of OATs by SUMOylation

SUMOylation is another type of post-translational modi

cation

known as a crucial regulatory mechanism of protein function on both

nuclear proteins and cellular membrane proteins (Gareau & Lima,

2010; Gill, 2004; Kang, Saunier, Akhurst, & Derynck, 2008; Plant et al.,

2010; Rajan et al., 2015; Rajan, Plant, Rabin, Butler, & Goldstein, 2005;

Ulrich, 2005, 2008). Till now three functional isoforms (SUMO1-3)

have been identi

ed in mammals, and all three isoforms are expressed

in a wide range of tissues, such as brain, lung, liver, Pancreas, and kid-

ney. SUMO2 and SUMO3 are usually written as SUMO2/3 since they

share 97% identity in their amino acid sequences, while SUMO2/3 only

shares 50% homology with SUMO1. Although SUMO proteins are con-

sidered as the member of the ubiquitin-like protein family, they only

share approximately 18% identity with ubiquitin, and all three SUMO

proteins are polypeptides of ~12 kDa. Like ubiquitination, the conjuga-

tion of SUMO to target proteins also involves a series of enzymatic

steps. The inactive precursors of SUMO proteins are initially processed

by members of the SUMO1/sentrin speci

c peptidase (SENP) family to

truncate a ten amino acid long fragment from the C terminus, therefore

exposing a C-terminal diglycine motif to mature the SUMO proteins.

Then the SUMO-activating enzyme (E1) catalyzes the ATP-dependent

formation of a thioester bond between the C terminus of matured

SUMO and the active cysteine residue of a SUMO-activating enzyme

(E1). The activated SUMO is later transferred to a SUMO-conjugating

enzyme (E2). Eventually, SUMO is attached to the speci

c lysine residue

on the target protein with the facilitation of SUMO protein ligase (E3). A

SUMO substrate can be modi

ed by various types of SUMO conjugation:

monoSUMOylation (conjugation of one single SUMO to one single ly-

sine on the target protein), multiSUMOylation (conjugation of several

monoSUMO molecules to multiple lysine residues on the target pro-

tein), and polySUMOylation (extended polySUMO chain). Majority of

SUMO substrates contain the consensus motif, Ψ-K-x-D/E (where ψ is

a large hydrophobic residue, K is the lysine conjugated to SUMO, x is

any amino acid, E is a glutamic acid, and D is an aspartic acid). SUMO2

and SUMO3 contain internal SUMO consensus motifs, and therefore

are capable of forming polySUMO chains, whereas SUMO1 does not

share such property.

Recently published work showed that in COS-7 cells, OAT3 transport

activity and expression at the plasma membrane were increased by

short term PKA activation. Such increase resulted from the enhanced

rate of OAT3 recycling with no change in the rate of OAT3 internaliza-

tion. In addition, OAT3 was identi

ed as a SUMO substrate, and the con-

jugation of SUMO2/3 to OAT3 was also PKA-dependent. PKA activation

enhanced OAT3 SUMOylation, and such enhancement can be abrogated

by the presence of PKA-speci

c inhibitor H-89 (Fig. 4) (H. Wang, Zhang,

& You, 2019a). In Oat3 knockout mice, bile acids such as cholic acid and

taurocholic acid accumulated. Both substances are endogenous sub-

strates of Oat3 and can activate G protein-coupled receptors (GPCRs)

Fig. 4. Regulation of OATs by SUMOylation and deSUMOylation enzyme Senp2. S: SUMO, Senp2: SUMO1/sentrin speci

c peptidase 2, PKA: Protein kinase A.

(Deutschmann et al., 2018; Duboc, Tache, & Hofmann, 2014). The acti-

vation of GPCRs elevated the cAMP level leading to PKA signaling path-

way activation. PKA enhanced OAT3 SUMOylation, recycling rate, and

transport activity. Thus, the accumulation of bile acids contributed by

OAT3 reduction could potentially result in the upregulation of OAT3 ex-

pression and function to form a negative feedback loop. This connection

between OAT endogenous substrates and PTMs of OATs is an interesting

area to explore. We now know OAT3 is the substrate of SUMOylation.

However, which lysine residues on OAT3 are responsible for SUMO2/3

conjugation is still unknown. Further investigations of mapping the

SUMO conjugation sites on OAT3 is needed.

7.4.2.

Regulation of OATs by deSUMOylation

SUMOylation is a dynamic and reversible event, and SUMO is re-

moved from target protein by SUMO-speci

c proteases including mem-

bers of ubiquitin-like speci

c protease (Ulp, in yeast) and SENP family

(in mammals) (Han, Feng, Gu, Li, & Chen, 2018; Hannoun,

Greenhough, Jaffray, Hay, & Hay, 2010; Miura & Hasegawa, 2010;

Ulrich, 2005). So far, six human Senp proteins have been isolated and

shown to have the ability to de-conjugate SUMO. Among them (Yeh,

2009), Senp2 is identi

ed to travel between the nucleus and the cyto-

plasm, modulating the activities of some plasma membrane proteins in-

cluding receptors, channels, and transporters (Benson et al., 2007;

Itahana, Yeh, & Zhang, 2006; Qi et al., 2014; Tan et al., 2017).

It was recently revealed that in COS-7 cells, overexpression of Senp2,

a member of the SENP family, resulted in a decreased OAT3

SUMOylation, which paralleled well with a reduced OAT3 expression

and transport activity. Furthermore, knocking down the endogenous

Senp2 with Senp2-speci

c siRNA led to an enhanced OAT3

SUMOylation, which paralleled well with an increased OAT3 expression

and transport activity. Coimmunoprecipitation experiments revealed

that Senp2 directly interacted with OAT3/Oat3 both in COS-7 cells and

in rat kidneys (Fig. 4) (Wang & You, 2019).

Senps have been reported as key regulators in upholding a balance

between SUMOylated and unSUMOylated proteins that are crucial for

physiological homeostasis. Many investigations indicated the alter-

ations in the amount of Senps under pathophysiological conditions,

and Senps were associated with the progress of a number of diseases,

especially cancer. For example, the level of Senp2 was decreased in

bladder cancer and hepatocellular carcinoma (HCC) tissues, and the

hyperexpression of Senp2 resulted in the suppressions on both bladder

cancer metastasis and HCC development (Shen, Zhu, Yang, & Ji, 2012;

Tan et al., 2017). Other than cancers, the overexpression of Senp2

played an important role in the development of congenital heart defects

and cardiac dysfunction by enhancing deSUMOylation (Kim et al.,

2012). Thus, Senps have received increasing recognition as interesting

targets for drug discovery. 1,2,5-Oxadiazoles were developed as a new

class of Senp2 inhibitors, which could have the therapeutic potential

for many diseases (Kumar, Ito, Takemoto, Yoshida, & Zhang, 2014). Fur-

ther studies exploring the effects of Senp2 inhibitors on OAT transport

activity, surface expression, and SUMOylation would be very exciting.

7.5.

Regulation of OATs by Glycosylation

Glycosylation, a common and complex PTM of proteins, is the cova-

lent attachment of carbohydrates to speci

c residues of a target protein,

which expands the proteasome complexity and modulates the target

protein via changes in cellular location, protein stability, protein

structure, and protein activity (Eichler, 2019). Glycosylation are classi-

ed into several different protein-sugar linkages, such as N-

glycosylation, O-glycosylation, C-glycosylation, S-glycosylation, and P-

glycosylation. N-glycosylation and O-glycosylation are predominantly

found in eukaryotes, and N-glycosylation accounts for more than half

of the protein glycosylation in eukaryotes. N-glycosylation refers to

the attachment of a glycan to the asparagine residue of the target pro-

tein within a consensus peptide sequence (Asn-X-Ser/Thr, X can be

any amino acid except proline). For membrane proteins, endoplasmic-

Golgi pathway, glycosidases, and glycosyltransferases are involved in

the glycosylation process (Christiansen et al., 2014). Many membrane

proteins have been identi

ed as the substrates of glycosylation, and gly-

cosylation plays a critical role in regulating the function and activity of

those membrane proteins (L. B. Li et al., 2004).

OAT1 has been reported as the substrate of glycosylation. Asp-39 on

OAT1/Oat1 is crucial for substrate recognition of glycosylation, and gly-

cosylation is essential for the targeting of OAT1/Oat1 onto the plasma

membrane (Tanaka, Xu, Zhou, & You, 2004). Furthermore, mutagenesis

of glycosylation sites on OAT4 and treatment of tunicamycin, a glycosyl-

ation inhibitor, resulted in a non-glycosylated OAT4 and the failure of

targeting OAT4 onto the plasma membrane in cultured cells. In addition,

OAT4 expressed in CHO-Lec1 cells, carrying oligosaccharides bearing

mannose-rich intermediates, had reduced binding af

nity towards the

substrates compared with OAT4 in CHO wild-type cells, and it was con-

cluded that processing of added oligosaccharides from mannose-rich

type to complex type was important for modulating OAT4 substrate

binding af

nity (F. Zhou et al., 2005). Congenital disorders of glycosyla-

tion (CDG), an ever-expanding disease, are a group of inherited meta-

bolic disorders, which affecting glycosylation process. As many steps

and enzymes are involved in the glycosylation process, CDG patients

commonly are de

cient of one or more enzymes for one or more glyco-

sylation steps and show variable clinical symptoms including multi-

organ dysfunction (Bryant et al., 2020; Ferreira et al., 2018). Kidney dis-

function, nephropathy, and lesion of proximal tubule, where OATs are

mainly expressed, are symptoms of CDG, and glycosylation is critical

for modulating transport activity of OATs. Thus, OAT function and ex-

pression in CDG patients would be interesting and exciting to

investigate.

7.6.

Crosstalk between various PTMs

During the past decade, evidence for comprehensive crosstalk be-

tween different PTM types has stacked up, especially the interplay

between the PTMs occurring on the same type of amino acid residue

(s). One of the examples is the crosstalk between ubiquitination and

SUMOylation, in which both ubiquitin and SUMO covalently conjugate

to the lysine residue (s) of a substrate protein. One scenario is that ubiq-

uitin and SUMO modify the same lysine residue(s) in a target protein

through competitive manner. On the other hand, SUMO and ubiquitin

may modify different lysine residues in a substrate protein. In such

case conjugation of SUMO may potentially mask a nearby ubiquitin con-

jugation site. Under both circumstances, SUMOylation may preclude the

ubiquitin-mediated degradation of target protein (Hunter & Sun, 2008).

It was demonstrated that the enhancement of OAT3 SUMOylation by

PKA activation paralleled with a decrease in OAT3 ubiquitination in cul-

tured cells. Therefore, SUMOylation and ubiquitination may coordi-

nately regulate OAT3 through crosstalk (H. Wang et al., 2019a).

Other PTMs, which also occur on lysine residue(s) of the target pro-

tein, could potentially be involved in the crosstalk with both

ubiquitination and SUMOylation. Besides the direct competitions on

the same lysine residue(s) among these modi

cations, underlying

mechanism can be more complex and may not follow a uniform rule

(Appikonda et al., 2018; Caron, Boyault, & Khochbin, 2005; Gareau &

Lima, 2010). In addition, the interplay could also happen between two

or more PTMs modifying different types of amino acid residues

(Hietakangas et al., 2003; Muller, Matunis, & Dejean, 1998; Nguyen,

Kolch, & Kholodenko, 2013; Rajan et al., 2015; Yang, Jaffray,

Senthinathan, Hay, & Sharrocks, 2003). It would be interesting to ex-

plore new potential crosstalk among various PTMs of OATs.

7.7.

Remote Sensing and Signaling Hypothesis of OATs

In the recent years, systems biology studies together with the in-

vestigations of OAT knockout mice have indicated that the roles of

OATs in different organs may form a network, and this network

allows the intercellular and inter-organ communication. Such com-

munication between cells, as well as between organs, regulates the

local and whole-body homeostasis. This hypothesis is called remote

sensing and signaling (Ahn & Nigam, 2009; S. K. Nigam, 2018; S. K.

Nigam et al., 2015).

The overlapping of substrate speci

cities among different OAT iso-

forms, the wide tissue distributions of different OAT isoforms

(e.g., kidney, liver, brain, placenta, retina, olfactory mucosa, etc.), and

the various regulations of OAT expression and function mediated by

signaling molecules secreted from remote tissues into the body

uid

contribute to the complicated communication network of OATs

(Burckhardt, 2012; Roth, Obaidat, & Hagenbuch, 2012; You, 2002). For

example, it was reported that indoxyl sulfate, a gut microbiome-

derived metabolite and endogenous OAT substrate, up-regulated OAT1

via AhR and EGFR signaling under the control of miR-223 in cultured

cells, and the up-regulation on OAT1/Oat1 was to react to the elevated

indoxyl sulfate level and to maintain homeostasis through inducing

renal secretion. This phenomenon was observed in cultured cells, rat

kidneys, and human kidneys (Jansen et al., 2019). Oat3 was involved

in the regulation of blood pressure through the remote sensing and sig-

naling. The blood pressure of Oat3 knockout mice was 15% lower than

that of control mice. Metabolomic analysis indicated that plasma con-

centrations of Oat3 substrates were increased in Oat3 knockout mice,

and some endogenous Oat3 substrates could serve as vasodilators, such

as thymidine, cAMP, and cGMP, to reduce the blood pressure (Vallon

et al., 2008; Vallon, Eraly, et al., 2008). In addition, the renal excretion

of vasodilators, the substrates of Oat3, was reduced responding to the el-

evated blood pressure, caused by internally and externally environmen-

tal changes. And then the accumulated vasodilators subsequently

decreased the blood pressure thereby maintaining homeostasis (Ahn &

Nigam, 2009; Eraly, 2008).

Hormones and growth factors produced and released from the orig-

inal organ under the internal and external stimuli arrive at the target

organ and regulate the OATs in the target organ through binding to

the receptors and activating the downstream signaling pathways. For

example, Oat3 expression and transport activity were impaired in the

streptozotocin-induced type 1 diabetic rats compared with those in

wild-type rats, and insulin treatment abolished the effects.

Streptozotocin was used to damage insulin-producing beta cells in the

pancreas to induce diabetes in animal models. Protein kinase C alpha

(PKCα) and phospho-PKCα expression were increased in diabetic rats,

and insulin treatment reversed the effects (Phatchawan et al., 2014).

In addition, insulin stimulated OAT4 expression and transport activity

through impairing the interaction between Nedd4-2 and OAT4, and

Nedd4-2 knockdown abolished the stimulation effect of insulin on

OAT4 in cultured cells (H. Wang et al., 2019b). IGF-1, produced in the

liver under stimuli, up-regulated renal OAT3 function through PKA fol-

lowing binding to its receptor in cultured cells, which was abrogated

by PKA inhibitor H89 and linsitinib (J. Zhang et al., 2020). Besides, it

was demonstrated that Angiotensin II, produced in adrenal gland, re-

duced OAT1 and OAT3 function through PKC in cultured kidney cells

(P. Duan et al., 2010; S. Li et al., 2009). Furthermore, parathyroid Hor-

mone, produced in parathyroid glands in the neck, enhanced OAT4 ac-

tivity through a PKA independent pathway in cultured kidney cells (P.

Duan, Li, & You, 2012). In remote sensing and signaling model, OATs

play an essential role in intercellular and inter-organ communication

and in maintaining local and whole-body homeostasis. Such complex

and dedicated communication is carried out by hormones, small mole-

cules and cell signaling.

Conclusion

Elucidating the mechanisms by which OATs are regulated contrib-

utes signi

cantly to our knowledge of the processes involved in physiol-

ogy, pathology, and drug disposition. It has become increasingly clear

that OATs are regulated by a variety of extracellular factors originated

from different organs, by multiple intracellular signaling pathways,

and by various PTMs. Our overview of several important OAT regulators

provides insights into the complexity of this process. Most studies have

examined these regulatory factors in isolation. How they work in con-

cert to modulate OAT function, to improve OAT-related medical treat-

ment, and to keep body homeostasis are important questions that

continue to be addressed.

Declaration of Competing Interest

The authors declare that there are no con

icts of interest.

Acknowledgements

This work was supported by grants (to Dr. Guofeng You) from Na-

tional Institute of General Medical Sciences (R01-GM079123, R01-

GM097000 and R01-GM127788).

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Pharmacology & Therapeutics xxx (xxxx) xxx
Contents lists available at ScienceDirect
j o u r na l h om ep a ge : ww w. e ls e v i e r. c om / loc at e/ p h arm t he ra
Regulation of organic anion transporters: Role in physiology,
pathophysiology, and drug elimination
Jinghui Zhang, Haoxun Wang, Yunzhou Fan, Zhou Yu, Guofeng You ⁎
Department of Pharmaceutics, Rutgers, the State University of New Jersey, Piscataway, NJ, USA A R T I C L E I N f О A B S T R A C T Available online xxxx
The members of the organic anion transporter (OAT) family are mainly expressed in kidney, liver, placenta, intes-
tine, and brain. These transporters play important roles in the disposition of clinical drugs, pesticides, signaling Keywords:
molecules, heavy metal conjugates, components of phytomedicines, and toxins, and therefore critical for main- Drug transporter
taining systemic homeostasis. Alterations in the expression and function of OATs contribute to the intra- and Organic anion transporter
inter-individual variability of the therapeutic efficacy and the toxicity of many drugs, and to many pathophysio- Drug disposition
logical conditions. Consequently, the activity of these transporters must be highly regulated to carry out their
Post-translational modification
normal functions. This review will present an update on the recent advance in understanding the cellular and Regulation
molecular mechanisms underlying the regulation of renal OATs, emphasizing on the post-translational modifica-
tion (PTM), the crosstalk among these PTMs, and the remote sensing and signaling network of OATs. Such knowl-
edge will provide significant insights into the roles of these transporters in health and disease.
© 2020 Elsevier Inc. All rights reserved. Contents 1.
Introduction ........................................................................................................................................................................................... 0 2.
OAT expression, structure, and function ........................................................................................................................................... 0 3.
OATs and drug-drug interaction (DDI) ............................................................................................................................................... 0 4.
OATs in kidney injury and diseases ................................................................................................................................................... 0 5.
Genetic polymorphisms of OATs and clinical impact ...................................................................................................................... 0 6.
Roles of OATs in the handling of endogenous substances and their metabolites ....................................................................... 0 7.
Regulations of OATs .............................................................................................................................................................................. 0 8.
Conclusion .............................................................................................................................................................................................. 0
Acknowledgements ........................................................................................................................................................................................ 0
Reference ......................................................................................................................................................................................................... 0 1. Introduction
multiple tissues, such as kidney, liver, brain, placenta, retina, and olfac-
tory mucosa (He et al., 2014; S. K. Nigam et al., 2015). They are the key
Organic anion transporters (OATs), a subfamily of the solute carrier
players for the translocation of various substances into and out of cells,
22 (SLC22) transporters, are localized on the physiological barriers of
such as signaling molecules, toxins, and a diverse array of important
clinical therapeutics, including antivirals, anti-cancer drugs, antibiotics,
anti-hypertensives, and anti-inflammatories. (Ahn & Nigam, 2009; Cha
Abbreviations: OAT, organic anion transporter; TMD, transmembrane domain; DDI,
et al., 2000; Dantzler & Wright, 2003; He et al., 2014; Pritchard, 1990;
drug–drug interaction; Nedd4-1/Nedd4-2, neural precursor cell expressed developmen-
Srimaroeng, Perry, & Pritchard, 2008; Taki, Nakamura, Miglinas, tally down-regulated 4-1/4-2; PTM, post-translational modification; DUB,
deubiquitinating enzyme; Sgk, serum- and glucocorticoid-inducible kinase; PKA, protein
Enomoto, & Niwa, 2006; Terada & Inui, 2007; Vallon et al., 2008;
Kinase A; PKB, protein Kinase B; PKC, protein Kinase C; USP8, ubiquitin-specific protease
VanWert, Gionfriddo, & Sweet, 2010; You, 2002). Therefore, OATs are
8; SENP, SUMO1/sentrin specific peptidase; IGF-1, Insulin-like growth factor 1.
not only critical for physiological and pathological processes in the
* Corresponding author at: Department of Pharmaceutics, Rutgers, The State University
body, but also critical in absorption, distribution, metabolism, and
of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
E-mail address: gyou@pharmacy.rutgers.edu (G. You).
elimination (ADME) of clinical therapeutics, thus affecting the https://doi.org/10.1 016/j.pharmthera.20 20.107647 0163- 7258/© 2020 Elsevier Inc. All rights reserved.
Fig. 1. Major drug transporters expressed in human renal proximal tubule cells. MRP: multidrug resistance-associated protein, OCT: organic cation transporter, OAT: organic anion
transporter, OATP: organic anion-transporting peptide, MATE: multidrug and toxin extrusion protein, PEPT: peptide transporter, BCRP: breast cancer resistance protein, MDR:
multidrug resistance mutation, URAT: urate transporter.
pharmacokinetics and pharmacodynamics of the drug profile. Among
2012; Koepsell, 2013; S. K. Nigam et al., 2015; L. Wang & Sweet,
the tissues involved in the ADME of clinical therapeutics, the kidney is
2013b; D. Xu, Wang, & You, 2016b).
one of the vital organs responsible for drug elimination after its admin-
Kidney is responsible for eliminating substances from the blood and
istration. Renal drug transporters are in charge of the transfer of the
reabsorbing certain compounds back into the circulation. In this way it
drugs between blood and proximal tubule lumen. Among various
keeps essential nutrients in the circulation while removing harmful me-
renal drug transporters, OATs, mainly interacting with organic anionic
tabolites and therapeutic agents from the body (L. Wang & Sweet,
molecules, are expressed at both the basolateral membrane and apical
2013b). There are three major events in this process: glomerulus filtra-
membrane of the proximal tubule cells and are responsible for the ex-
tion, tubule secretion, and reabsorption. Unlike the passive filtration
cretion of numerous endogenous and exogenous substances. Because
processes occurring in kidney glomeruli, much of the active exchange
of the importance of OATs in disposition of many important clinical
of compounds happen in the kidney proximal tubule, where a number
drugs and in various physio-pathological processes, numerous efforts
of important transporters are expressed (Fig. 1). Proximal tubule cells
have been made to uncover molecular and cellular mechanisms that
polarize into apical membrane, which faces the urine, and basolateral
contribute to the regulation of OATs. In this review, we discussed the re-
membrane, which faces the blood vessel. The OAT members are
cent advance in understanding the regulation of OATs, highlighting the
expressed in renal proximal tubule, both on the basolateral and on the
regulation at the level of post-translational modification and the regula-
apical membrane. They stand as important mediators in the active pro-
tory network of the remote sensing and signaling.
cess of renal elimination and reabsorption (Emami Riedmaier et al.,
2012; Motohashi et al., 2013).
2. OAT expression, structure, and function
In human, OAT1, OAT2, OAT3, OAT4, OAT10, and URAT1 have been
detected in kidney samples. It is worth to mention that in rodents cer-
The OAT family consists of a group of transmembrane proteins with
tain Oats have different expression profiles from those in human.
around 540-560 amino acids. The OATs have been identified in the epi-
These comparisons could help to understand the differences of OAT
thelia barriers such as kidney, liver, brain, placenta, and intestine. These
functions and regulations between rodent models and clinical studies.
OATs play significant roles in modulating the movement of organic
(S. K. Nigam et al., 2015; L. Wang & Sweet, 2013b). OAT1, OAT2, and
anion molecules across cell membranes. One of the characteristics of
OAT3 have been located on the basolateral membrane of the proximal
OATs is their wide range of substrate recognition including both physi-
tubule cells in human kidney, which is the blood side of these cells
ological/endogenous substrates and their metabolites and xenobiotic
(Fig. 1). These three OATs facilitate the transfer of organic anions from
molecules such as environmental toxins and therapeutic drugs, which
blood into the proximal tubule cells driven by a tertiary transporting
makes them important players in body homeostasis and pharmacolog-
mechanism. Across basolateral membrane, the cells utilize the sodium
ical responses (VanWert et al., 2010). Understanding the relationships
gradient generated by Na+-K+-ATPase to indirectly drive the influx of
between the molecular features of OATs and their functions provided
organic anions into the proximal tubule cells. OAT4 and URAT1 (another
significant insights into their influences on clinical drug elimination, ef-
member of OAT family) are expressed on the apical membrane or the
ficacy, and toxicity. (Emami Riedmaier, Nies, Schaeffeler, & Schwab,
urine side of the proximal tubule cells (Fig. 1). OAT4 mediates
reabsorption of organic anions from urine back into the tubule cells.
enhanced toxicity and increased risk of developing rhabdomyolysis
OAT10, with higher expression in kidney proximal tubule and small in-
(Feng et al., 2016). In addition to approved drugs, indoxyl sulfate, a ure-
testine, has been proved to transport nicotine and uric acid. URAT1 is
mic toxin, was confirmed as a substrate of OAT1, OAT3, and OAT4 in cul-
mainly responsible for the reabsorption of urate via monocarboxylates
tured cells (Hsueh et al., 2016). In a rat study, the blood concentration of
exchange. (S. K. Nigam et al., 2015; L. Wang & Sweet, 2013b).
indoxyl sulfate increased with lower renal clearance when adminis-
Through computer modeling and site-directed mutagenesis studies,
trated with quinapril, whose metabolite quinaprilat was also a substrate
it has been revealed that OAT family shares a similar structure feature
of Oat3 (Fujita et al., 2012; Yuan et al., 2009). To connect in vitro studies
consisting of intracellular N- and C-termini, 12 α-helical transmem-
with in vivo research, Mathialagan, et al. applied transporter data ob-
brane domains (TMDs), a large extracellular loop between TMD1/2,
tained from OAT-expressing human cells to quantitatively predict
and a central intracellular loop between TMD6/7 (Anzai, Kanai, &
in vivo renal elimination and total renal clearance. Their results con-
Endou, 2006; F. Zhou & You, 2007; Zhu et al., 2015). Three highly con-
cluded that renal transport mediated by OAT3 played a predominant
served regions are mainly responsible for protein functions: the large
role in renal elimination for a majority of drugs they tested
extracellular domain between TMD1/2, the central intracellular loop be- (Mathialagan et al., 2017).
tween TMD6/7, and TMD9/10. These three regions work together to en-
Recognized as a powerful organic anion transport inhibitor, proben-
sure substrate specificity and proper transport activity of OATs
ecid was used with clinical therapies to prolong half-life of drugs there-
(Koepsell, 2013; Zhu et al., 2015). Furthermore, the large extracellular
fore enhance therapeutic effects (L. Wang & Sweet, 2013b). In healthy
domain between TMD1/2 contains multiple glycosylation sites, which
volunteers, probenecid inhibited the clearance of mesna, an OAT sub-
are important for OAT trafficking to cell surface (F. Zhou et al., 2005).
strate, increasing its protective effect against the toxicity of cyclophos-
The C-terminus and central intracellular loop between TMD6/7 contain
phamide and cisplatin (Cutler et al., 2012). However, inhibition of
potential phosphorylation sites, which are involved in regulations of
OATs works as a double-edged sword, which may cause higher system-
transport function and expression (Zhu et al., 2015). OAT1 formed
atic toxicity when exposing whole body to a drug for an extended time
homo-oligomers on plasma membrane when expressed in cell culture,
(Takahara et al., 2013). In a clinical study of patients with non-small cell
which were confirmed via co-immunoprecipitation and gel filtration
lung cancer, hematologic toxicity caused by pemetrexed was amplified
chromatography (Hong et al., 2005). TMD6 is important to homo-
when lansoprazole was co-administrated. Cell line-based study later
oligomerization of OAT1 on plasma membrane, which plays a signifi-
confirmed that lansoprazole inhibited OAT3, thus decreased the renal
cant role on transporter expression and activity (P. Duan, Li, & You,
uptake and elimination of pemetrexed, and eventually increased hema-
2011). In addition, TMD12 has been shown to play a critical role in
tologic toxicity in patients (Ikemura et al., 2016). A clinical study found
OAT maturation and stability (Hong, Li, Zhou, Thomas, & You, 2010).
that AK106–001616, a cytosolic phospholipase A2 inhibitor, inhibited
OAT1 and OAT3 and increased the area under curve of methotrexate
3. OATs and drug-drug interaction (DDI)
in rheumatoid arthritis patients (Kozaki et al., 2015). In cancer patients
who received methotrexate, a drug for arthritis and cancer, with proton
Clinically observed DDIs can be dated back to more than 50 years ago
pump inhibitors, their plasma concentrations of methotrexate were sig-
with the co-administration of probenecid and penicillin. Probenecid, an
nificantly higher than those in patients taking methotrexate alone,
inhibitor for organic anion transport system, inhibited the renal clear-
which was consistent with another cell-based study using cultured
ance of penicillin, consequently increased the efficacy of penicillin
cells expressing OAT1 and OAT3. It was found that proton pump
(Gibaldi & Schwartz, 1968). With progress in molecular cloning and
inhibitors like omeprazole significantly decreased the uptake of metho-
characterization of individual OATs, molecular and cellular mechanisms
trexate through inhibiting OAT1 and OAT3 (Chioukh et al., 2014;
underlying OAT-mediated DDIs have been revealed. Due to the vast
Narumi et al., 2017). In summary, with expanding knowledge and
range of substrate recognition of OATs, multiple therapeutic agents,
discoveries, OAT-mediated DDIs continue to play significant roles in
when taken together, may mutually affect each other’s pharmacokinetic
the pharmacokinetic profiles, efficacy, and toxicity of a wide range of
profiles through interacting with the same transporters, either in a com- clinical therapeutic agents.
petitive or non-competitive manner, which causes drug–drug interac-
tion (Huo & Liu, 2018; L. Wang & Sweet, 2013b). It would be
4. OATs in kidney injury and diseases
impractical to assess all the DDI possibility of approved drugs and new
drug candidates only in clinical studies. Thus, cell line-based in vitro
Clinical observations between kidney diseases and renal OATs are
DDI assays are proven to be valuable research tools (Giacomini et al.,
often complex and intertwined. On one hand, kidney injury and dis-
2010; Huo & Liu, 2018). In recent years, the US Food and Drug Adminis-
eases could directly affect renal OAT expression, function, and localiza-
tration (FDA) with International Transporter Consortium have issued
tion. On the other hand, direct damage on proximal tubule cells and
guidance for the assessment of transporter-mediated drug–drug inter-
OATs could also change various renal functions, leading to kidney dis-
actions during drug development process. Among the important drug
ease progression. Plentiful animal and clinical studies have revealed
transporters, OAT1 and OAT3 were listed as potential targets for DDI
possible correlations between them (Huo & Liu, 2018; Schwenk & Pai,
assessment (Giacomini et al., 2010; Hillgren et al., 2013).
2016; L. Wang & Sweet, 2013b; D. Xu, Wang, & You, 2016b).
Numerous in vitro OAT-mediated DDI studies of therapeutic drugs,
Acute kidney injury (AKI) is a common and complex condition
such as anti-tuberculosis drugs, anti-viral drugs, and anti-cancer
especially for patients in the intensive care units. The well-recognized
drugs, have been reported (Maeda et al., 2014; Parvez, Kaisar, Shin,
causes of AKI are drug/toxicant-induced renal toxicity and renal
Jung, & Shin, 2016; Toh et al., 2016; L. Wang, Pan, & Sweet, 2013; L.
ischemia/reperfusion (L. Wang & Sweet, 2013b). Renal ischemia/reper-
Wang & Sweet, 2013a). In a recent study, OAT4-expressing cells were
fusion often decreases Glomerular filtration rate (GFR) and damages
utilized to screen a panel of anti-cancer drugs. Epirubicin hydrochloride
tubular functions like secretion and reabsorption (Bischoff, Bucher,
and dabrafenib mesylate showed cis-inhibitory effect on OAT4 uptake
Gekle, & Sauvant, 2014b). In ischemic rat kidneys, the mRNA and
activity. Furthermore, it was discovered that dabrafenib mesylate
protein expression levels of Oat1 and Oat3 were both reduced
exerted competitive inhibition while inhibition by epirubicin hydro-
(Bischoff et al., 2014b; Schneider et al., 2015). Anti-inflammatory
chloride was in a noncompetitive manner, and epirubicin hydrochloride
drugs meclofenamate, quercetin, and resveratrol reduced indoxyl
had a higher chance causing clinical DDI (C. Liu, Zhang, & You, 2019). In
sulfate accumulation during AKI and ameliorated the reduction of
a rat study both mizoribine and bezafibrate were found to be Oat1 and
Oat1 and Oat3 protein expression in ischemic AKI rats (Saigo et al.,
Oat3 substrates. The co-administration of mizoribine and bezafibrate in-
2014; Saito et al., 2014). Prostaglandin E2 decreased the mRNA levels
creased the accumulation of bezafibrate in the circulation, causing
of Oat1 and Oat3 through E prostanoid receptor type 4 in rats with
ischemic-induced AKI (Bischoff, Bucher, Gekle, & Sauvant, 2014a;
expression and function of Oats under diabetic conditions have been
Preising, Schneider, Bucher, Gekle, & Sauvant, 2015). A wide range of
studied in various animal models. One animal study showed that the ac-
clinical therapeutics could cause renal toxicity and induce AKI, such as
tivity and protein level of Oat3 were decreased in streptozotocin-
aminoglycosides antibiotics and angiotensin-converting-enzyme inhib-
induced diabetic rats, which could be restored by insulin treatment
itors (Pannu & Nadim, 2008). Previous research revealed that gentami-
(Phatchawan, Chutima, Varanuj, & Anusorn, 2014). In another study
cin can cause necrosis of proximal tubule cells, which would inhibit
using Ins2Akita mouse, a model for diabetes, the mRNA and protein ex-
protein synthesis in kidney and induce AKI. Furthermore, gentamicin
pression levels of Oat1, Oat2, and Oat3 were all reduced (C. Xu et al.,
was able to increase the levels of superoxide anion and hydrogen perox-
2015). Furthermore, the mRNA level of Oat2 were decreased in both
ide in renal cortical cells, which would also contribute to renal toxicity
Ob/Ob obese mice and Db/Db diabetic mice (Cheng et al., 2008). In
(Baliga, Ueda, Walker, & Shah, 1999). In a rat model of gentamicin-
obese rats with high fat diet (HF), it was reported that Oat3 transport
induced AKI, both plasma creatinine and blood urea nitrogen levels
function and protein expression were decreased. Atorvastatin or
were increased, indicating reduced renal function and toxicity. In this
vildagliptin treatment in HF rats partially reversed the impaired renal
AKI model, both the mRNA and protein expressions of Oat1 and Oat3
Oat3 function (Pengrattanachot et al., 2020). In addition to diabetes,
were significantly decreased. It was possible that gentamicin-caused
cholestasis, a liver disease, in which the flow of bile from liver is reduced
toxicity down-regulated kidney Oat1 and Oat3 expression, which con-
or obstructed, was reported to affect renal Oats in animal models.
tributed to the reduced renal function and accumulated endogenous
Administration of alpha-naphthyl isothiocyanate (ANIT) to induce bili-
substances (X. Guo et al., 2013). Resveratrol, an anti-inflammatory and
ary obstruction in rats resulted in reduced protein expression of Oat1
antioxidant agent, reduced methotrexate-induced renal toxicity in rats
and Oat3 (T. Liu et al., 2012). In rats with bile duct ligation (BDL),
via decreasing Oat-mediated kidney elimination of methotrexate. This
protein expression of Oat1 was decreased while Oat3 expression was
reduced toxicity was mainly due to direct inhibition by resveratrol on
increased (Brandoni, Anzai, Kanai, Endou, & Torres, 2006). The method
Oat1 and Oat3 (Jia et al., 2016).
of BDL-induced biliary obstruction animal model is different from that
In patients with chronic kidney failure (CKF), the glomerular filtra-
of ANIT-induced intrahepatic cholestasis model, which possibly contrib-
tion rate and renal clearance decline gradually and continuously,
utes to the difference in the variation of OAT3 expression in both
which would cause endogenous metabolites, uremic toxins, and thera-
reports. In a rat model of bilateral ureteral obstruction, a disease that
peutic agents to accumulate in the circulation and often lead to renal
blocks the flow of urine from kidney to bladder, the transport activity
failure (Naud et al., 2011). In the process, uremic toxins exert effects
and protein expression levels of Oat1 and Oat3 in the kidney were
on OATs in two aspects. On one hand, uremic toxins could regulate
reduced (Villar, Brandoni, & Torres, 2008).
OAT expression. In a rat model of adenine-induced CKF, the mRNA
In addition to animal models, OAT expression was investigated in
and protein expression levels of Oat1 and Oat3 were significantly re-
multiple clinical studies. In patients with metastatic colorectal cancer,
duced (Komazawa et al., 2013). In a CKF rat model by 5/6 nephrectomy,
higher OAT2 expression was detected in tumor tissues after 5-
Oat1, Oat2, and Oat3 mRNA and protein expression levels were reduced.
fluorouracil/leucovorin/oxaliplatin (FOLFOX) treatment. And higher
Interestingly, incubating human proximal tubule cells with sera from
OAT2 level was significantly correlated with good objective tumor re-
CKF rats caused a similar decreasing effect on human OATs (Naud
sponse which could serve as an independent predictor of good
et al., 2011). The authors hypothesized that the decreasing effects on
FOLFOX treatment outcome, possibly due to the roles of OAT2 in uptake
OAT/Oat were possibly due to accumulated metabolites and uremic
of the FOLFOX drugs (Tashiro et al., 2014). In hepatocellular carcinoma
toxins in the sera of CKF rats, although regulatory mechanisms were
(HCC) patients who received curative local ablation therapy, those
not clearly revealed. In support, p-cresyl sulfate, a uremic toxin, reduced
with reduced OAT2 expression had significantly higher rates of multifo-
Oat1 expression in a separate animal study. Oat1 protein expression
cal recurrence than those with normal OAT2 expression. In addition, the
was decreased by 40% after p-cresyl sulfate administration by oral ga-
decreased level of OAT2 was significantly correlated with future devel-
vage in CKF rats (Jansen et al., 2019).
opment of HCC in chronic hepatitis C virus infected patients (Yasui et al.,
In addition to the regulation on OAT expression, accumulated me-
2014). The mRNA level of OAT1 was significantly lower in kidney biopsy
tabolites and uremic toxins could also inhibit OAT transport activity
specimens from patients with renal diseases compared to normal kid-
and cause OAT-mediated drug-drug interactions (DDI) (Huo & Liu,
ney cortex tissues, while the levels of OAT2/4 mRNA seemed to increase
2018). Accumulated indoxyl sulfate (IS) and hippuric acid decreased
slightly (Sakurai et al., 2004).
renal clearance of morinidazole metabolites, substrates of Oat1 and
In recent years, adjusting drug dosage became necessary in patients
Oat3, through Oat-mediated DDIs in CKF rats. Thus the plasma concen-
with renal injury and diseases. The changes in GFR as well as renal OAT
trations of morinidazole metabolites were significantly elevated (Kong
expression and functions should be taken into consideration to achieve
et al., 2017; Zhong et al., 2014). In CKF rats, green tea metabolites fur-
an effective therapy. Thus, further studies of mechanistic connections
ther reduced kidney clearance and increased the plasma levels of IS
between OATs and various diseases are required to improve therapeutic
and p-cresyl sulfate by inhibiting the functions of Oat1 and Oat3 (Peng
efficacy and reduce possible toxicity in patients with altered renal
et al., 2015). The complex relationship between uremic toxins and functions.
OATs has also been reported in Oat1 and Oat3 knockout mice (A. K.
Nigam et al., 2020; W. Wu, Bush, & Nigam, 2017). In Oat1 knockout
5. Genetic polymorphisms of OATs and clinical impact
mice, the levels of IS, kynurenine, and xanthurenic acid were increased
in the plasma, and these toxins could inhibit Oat1 function in vitro
In recent years, correlation analysis between OATs polymorphisms
(Wikoff, Nagle, Kouznetsova, Tsigelny, & Nigam, 2011). Indoleacetate
and diseases in clinical studies were performed to further validate the
and p-cresyl sulfate were significantly increased in the plasma of Oat3
physiological function of OATs. A human study including normal sub-
knockout mice, and their interactions with Oat3 were also confirmed
jects and patients with chronic kidney disease (CKD) demonstrated
by in vitro data (W. Wu et al., 2017). In conclusion, the interaction be-
that patients with CKD had a higher frequency of the −475 single nucle-
tween uremic toxins and renal OATs is complicated under CKF condi-
otide polymorphisms (SNP) in the 5’ regulatory region in OAT1 than
tions. The accumulated metabolites and uremic toxins due to
normal subjects. Moreover, −475 SNP in OAT1 with T to G transversion
decreased expression and function of OATs in CKF would in turn further
reduced the binding of hepatoma-derived growth factor (HDGF, a
reduce OAT function, which forms a positive feedback loop between
known transcription repressor), and HDGF can down-regulate OAT1 uremic toxins and OATs.
protein expression, suggesting an increase of OAT1 expression and
A wide range of other pathological conditions were also revealed to
renal uptake of toxins, and nephrotoxicity with the −475 SNP (Sun
affect functions and expressions of renal OATs in animal studies. The
et al., 2018). In HEK293 cells, the OAT3-Ile305Phe variant had a reduced
maximum transport activity for cefotaxime, a substrate of OAT3 without
substrates of OATs needs further to be validated. Besides, many metab-
affecting the Michaelis-Menten constant value of OAT3, and a signifi-
olites are active signaling molecules, which will be discussed in detail in
cantly decreased surface expression of OAT3. As OAT3-Ile305Phe vari-
section of “Remote Sensing and Signaling Hypothesis of OATs”. There-
ant accounts for about 3.5% allele frequency in Asians, a clinical study
fore, the abnormity of OATs under certain kidney diseases may impact
showed that OAT3-Ile305Phe variant significantly suppressed the
the handling of these endogenous substances and their metabolites.
renal clearance of cefotaxime, in healthy volunteers (Yee et al., 2013).
Besides, a SNP (Position at chromosome11: 64088038, A/G) of OAT4 7. Regulations of OATs
was associated with renal underexcretion type gout by analysis of
OAT4 gene in gout patients and healthy volunteers, suggesting that
Given the crucial roles of OATs in physiological and pathological pro-
OAT4 expressed at apical membrane of renal proximal tubule cells con-
cesses and in determining the therapeutical efficacy and toxicity of
tributed to urate transport in humans (Kolz et al., 2009; Sakiyama et al.,
many clinical drugs, elucidating the cellular and molecular mechanisms
2014). Cho et al found that five new SNPs in the human URAT1 gene
underlying OAT regulation is of great significance. The regulations of
were significantly associated with uric acid concentration in blood by
OATs can take place at multiple levels, such as at the levels of transcrip-
analyzing subjects with normal uric acid level and subjects with hyper-
tion, post-transcription, translation, and post-translation, and numer-
uricemia (Cho, Kim, Chung, & Jee, 2015). Among the five SNPs,
ous signaling pathways are involved in these regulations.
rs75786299 had the highest association with hyperuricemia, followed
Several transcription factors have been identified to be involved in
by rs7929627 and rs3825017, while rs11602903 and rs121907892
the regulations of OATs. For example, in hepatocyte nuclear factor 1α
were negatively correlated with hyperuricemia. OAT1 and OAT3 at the
(HNF1α)-null mice, the levels of renal Oat1, Oat3, and Urat1 mRNA
basolateral membrane of the kidney proximal tubule cells may affect se-
were markedly reduced as compared to those in wild-type mice, and
cretion of uric acid rather than reabsorption like URAT1 at the apical
HNF1α overexpression enhanced OAT1, OAT3, and URAT1 promoter ac-
membrane, which was confirmed in Oat1 knock-out (Oat1KO) and
tivity in vitro (Kikuchi et al., 2006; Kikuchi et al., 2007; Maher et al.,
Oat3 knock-out (Oat1KO) mice (Eraly et al., 2008). It is interesting
2006; Saji et al., 2008). In ex vivo experiments with kidney organ cul-
that there are few SNPs of OATs in uric acid-related human diseases
ture, HNF4α antagonist attenuated the expression of Oat1 and Oat3
(such as hyperuricemia or hypouricemia) and other types of diseases
mRNA (Martovetsky, Tee, & Nigam, 2013). In addition, HNF4α
according to genome-wide association studies, which is possibly due
transactivated OAT1 promoter through DR-2 and IR-8 elements
to the overall low-frequency genetic variants of OATs compared with
in vitro (Ogasawara, Terada, Asaka, Katsura, & Inui, 2007). Furthermore,
other transporters with high polymorphisms (Lipkowitz, 2012; Lozano
B-cell CLL/lymphoma 6 (BCL6) increased OAT1 promotor activity de-
et al., 2018). One study found that a SNP (rs3793961) of OAT3 had asso-
pendent on HNF1α element and HNF1α protein in vitro (Wegner,
ciation with lower serum uric acid levels among men with CKD
Burckhardt, & Henjakovic, 2014). Besides, cAMP responsive element
(Bhatnagar et al., 2016). Besides, intestinal secretion of uric acid by
binding protein 1 (CREB1) and activating transcription factor 1
ATP-binding cassette transporter G2 (ABCG2), a key luminal intestinal
(ATF1), and the corresponding DNA binding sequence motifs on OATs
secretory urate transporter may play a complementary role for renal ex-
were also involved in the regulation of OATs (Ogasawara, Terada,
cretion (Ichida et al., 2012). In the 5/6 nephrectomy rats with CKD, the
Asaka, Katsura, & Inui, 2006). Several great review articles have already
serum uric acid did not increase despite the urine uric acid excretion
covered the regulations of OATs at the levels of transcription, post-
in the kidney significantly decreased; under such condition, overexpres-
transcription, and translation (Burckhardt, 2012; S. K. Nigam et al.,
sion of Abcg2 in intestine was observed, suggesting that Abcg2 in intes-
2015; Terada & Inui, 2007; L. Wang & Sweet, 2013b). Therefore, we
tine possibly rescued uric acid excretion in renal failure (Yano, Tamura,
will place our focus on the post-translational modifications of OATs in
Kobayashi, Tanemoto, & Uchida, 2014). Consistent with the rat model of the following discussion.
renal failure, Bhatnagar et al found that there was a significant associa-
Post-translational modifications (PTMs), the alternations on the
tion between serum uric acid and a SNP (rs4148157) on ABCG2 in intes-
amino acids of the target protein after its synthesis, refer to a process
tine in patients of European with CKD, further supporting that
of the covalent attachment of various functional group(s) to the
intestinal-expressed ABCG2 remotely compensates to maintain uric
amino acid side chain, terminal amino, or carboxyl group of the target
acid homeostasis in human with renal decline (Bhatnagar et al., 2016).
protein (G. Duan & Walther, 2015; Spoel, 2018). Most of the PTMs are
These clinical studies showed that genetic variants in drug transporters
dynamic and reversible processes which can be catalyzed by specific en-
can cause individual differences in drug effectiveness, drug toxicity, and
zymes to promote or demote the modification. These modifications in- some diseases.
fluence the expression, cellular localization, stability, structure, activity,
or substrate specificity of the target proteins. PTMs provide complexity
6. Roles of OATs in the handling of endogenous substances and their
to the proteome for diverse functions of the proteins. Various PTMs can metabolites
modify different parts of the target proteins individually or simulta-
neously. As a result, the functional diversities of the target proteins
A variety of endogenous substances and their metabolites are elimi-
much exceed their molecular diversities. Various PTMs of OATs have
nated by renal OATs to avoid the systemic toxicity, and to maintain the
been described in details in our previous review articles (P. Duan &
body’s homeostasis. Using Oat1 knock-out (Oat1KO) and Oat3 knock-
You, 2010; D. Xu, Wang, & You, 2016b; D. Xu & You, 2017). In this re-
out (Oat1KO) mice permits to investigate the physiological role of
view article, we will update the recent progress in uncovering the
OAT1 and OAT3 without the interference from other functionally redun-
new PTMs of OATs, the relationship among these PTMs, and the regula-
dant transporters, (Bush, Wu, Lun, & Nigam, 2017; Eraly et al., 2006).
tory network on OATs through remote sensing and signaling.
Nigam’s group showed that the levels of more than 100 metabolites in
the plasma were altered which were involved in key metabolic path-
ways such as in vivo metabolism of gut microbiome products, flavo-
7.1. Regulation of OATs by direct phosphorylation
noids, bile acids, nutrients, amino acids, and lipids (Bush et al., 2017;
Eraly et al., 2006; A. K. Nigam et al., 2020; S. K. Nigam, 2018;
Phosphorylation process is a crucial PTM which adds negative
Rosenthal, Bush, & Nigam, 2019). Among those metabolites, many of
charged phosphoryl group(s) to the target protein catalyzed by protein
them are endogenous substrates of OATs, such as bile acids (cholic
kinases, and the addition happens to a serine, threonine, or tyrosine res-
acid and taurocholic acid) are substrates of OAT3, and Indoxyl sulfate
idue (Czuba, Hillgren, & Swaan, 2018). Phosphorylation is an important
is substrate of OAT1 and OAT3 (Chen, Terada, Ogasawara, Katsura, &
regulatory mechanism for various membrane proteins including recep-
Inui, 2008; Lin et al., 2018). Whether other metabolites are endogenous
tors, channels, and transporters through a direct or indirect manner, and
Fig. 2. Phosphorylation of Ubiquitin ligase Nedd4-2 mediates the regulation of OAT transport activity by various kinases. U: ubiquitin, P: Phosphoryl group, S: Serine, T: Threonine, PKC:
Protein kinase C, Sgk1/2: Serum- and glucocorticoid-inducible kinase 1/2, Nedd4-2: Neural precursor cell expressed developmentally down-regulated 4-2.
induces the change in protein conformation, protein activity, cellular
inhibiting OAT activity (H. Wang, Liu, & You, 2018; H. Wang, Xu, Toh,
localization of protein, protein stability, or protein-protein interaction.
Pao, & You, 2016; H. Wang & You, 2017; H. Wang, Zhang, & You,
Many membrane proteins are the substrates of protein kinase-
2019b; J. Zhang, Liu, & You, 2018).
induced direct phosphorylation (Aromolaran, Chahine, & Boutjdir,
Our published and unpublished results indicated PKC activation de-
2018; Mayati et al., 2017). And many protein kinases have been re-
creased OAT expression and transport activity through Nedd4-2 phos-
ported to phosphorylate various transporters. (Cetinkaya et al., 2003;
phorylation instead of directly phosphorylating OAT itself in cultured
Foster & Vaughan, 2017). It is recently demonstrated that Protein Kinase
cells (D. Xu, Wang, & You, 2016a; D. Xu, Wang, Zhang, & You, 2016; D.
A (PKA) activation by Bt2-cAMP induced a significant increase in OAT3
Xu et al., 2017; You et al., 2000; Q. Zhang, Li, Patterson, & You, 2013).
phosphorylation, which was correlated with an enhanced OAT3 trans-
Wolff et al further confirmed such observation by site mutagenesis
port activity in cultured cells. Moreover, Insulin-like growth factor 1
assay: mutagenesis of five canonical PKC phosphorylation sites individ-
(IGF-1), an upstream hormone of PKA signaling, increased OAT3 phos-
ually and in combination resulted in mutants that were insensitive to-
phorylation, and the stimulatory effect was abrogated by H89 (a selec-
ward specific PKC activator dioctanoylglycerol in cultured cells (Wolff
tive PKA inhibitor). IGF-1-stimulated OAT3 phosphorylation was also
et al., 2003). The short-term PKC/Nedd4-2 activation increased OAT
correlated with enhanced OAT3 transport activity and protein expres-
ubiquitination, leading to an accelerated endocytosis of OATs and a re-
sion, and the up-regulation effect was abrogated by PKA inhibitor H89.
duction of its cell surface expression and transport activity in cultured
Therefore, PKA activation by Bt2-cAMP and IGF-1 up-regulated OAT3
cells. In addition, the prolonged PKC/Nedd4-2 activation resulted in
expression and transport activity possibly by directly phosphorylating
the endocytosed OAT to target to proteolytic system for degradation
OAT3 in COS-7 cells (J. Zhang, Yu, & You, 2020).
(Fig. 2). (D. Xu, Wang, & You, 2016a; D. Xu, Wang, Zhang, & You,
Dephosphorylation, countering phosphorylation, refers to a process
2016; D. Xu et al., 2017). Angiotensin II, an endogenous hormone,
which removes phosphoryl group(s) from the target proteins, catalyzed
inhibited OAT1 and OAT3 transport activity through the activation of
by phosphatases. Phosphorylation and dephosphorylation form an op-
PKC/Nedd4-2 pathway (P. Duan, Li, & You, 2010; S. Li, Duan, & You,
posing regulatory network, thus affecting a variety of cellular processes
2009). Nedd4-2 phosphorylation happens not only on serine/threonine
in health and disease (Ardito, Giuliani, Perrone, Troiano, & Lo Muzio,
residues, but also on tyrosine residues. AG490, a specific inhibitor of the
2017; Vitrac, Mallampalli, & Dowhan, 2019). Phosphatase inhibitor
Janus tyrosine kinase 2 (JAK2), reduced OAT3 cell surface expression
okadaic acid inhibited Oat1-mediated transport of para-aminohippurate
and transport activity in cultured cells. The reduced transport activity
(PAH) in cultured cells, which was correlated with an increased phos-
resulted from an enhanced OAT3 ubiquitination, following a reduced
phorylation of Oat1 (You, Kuze, Kohanski, Amsler, & Henderson, 2000).
Nedd4-2 tyrosine phosphorylation and an enhanced interaction be-
tween OAT3 and Nedd4-2. The inhibition effect of AG490 on OAT3
7.2. Regulation of OATs by indirect phosphorylation
was abrogated by knocking down the endogenous Nedd4-2 using
Nedd4-2-specific siRNA (J. Zhang et al., 2018).
Other than directly phosphorylating OATs, protein kinases could also
Some modulators of OATs reduce OAT transport activity through
regulate OATs through phosphorylating OAT-interacting proteins. For
Nedd4-2 phosphorylation, whereas others enhance OAT function
example, Nedd4-2, a ubiquitin ligase, is an OAT-interacting partner.
through phosphorylating Nedd4-2 at different sites. Overexpression of
Ubiquitination of OATs, catalyzed by Nedd4-2, led to the internalization
serum and glucocorticoid-regulated kinase 1 (Sgk1) stimulated OAT3
of OATs from cell surface to intracellular endosomes and subsequent
transport activity in cultured cells. It was shown that Sgk1 phosphory-
degradation. Several protein kinases, hormones, and chemicals excreted
lated Nedd4-2 on Ser327, which weakened the interaction between
their regulation on OATs through phosphorylating Nedd4-2 at different
OAT3 and Nedd4-2, and therefore decreased OAT3 ubiquitination
sites, which either weakened or strengthened the protein-protein inter-
(Fig. 2) (H. Wang & You, 2017). Furthermore, Dexamethasone, an up-
action between OATs and Nedd4-2, and led to either stimulating or
stream hormone of Sgk1, stimulated OAT3 expression and transport
Fig. 3. Regulation of OATs by Ubiquitination, deubiquiting enzyme USP8, and proteasome inhibitors. U: ubiquitin, USP8: ubiquitin-specific proteases 8, Nedd4-1/Nedd4-2: Neural precursor
cell expressed developmentally down-regulated 4-1/4-2.
activity through Nedd4-2 phosphorylation in cultured cells (H. Wang
activity, stability, cellular location, and their interactions with other
et al., 2018). Overexpression of Sgk2, an isoform of Sgk1, enhanced the proteins.
surface expression, total protein expression, and transporter activity
The ubiquitin-proteasome system (UPS) is a major protein degrada-
of OAT1 and OAT4 through impairing the binding between OATs and
tion system. Ubiquitination occurs in a sequence of three enzymatic
Nedd4-2 and decreasing OAT ubiquitination in cultured cells (Fig. 2).
steps and ubiquitinated proteins are targeted to the 26S proteasome
overexpression of Nedd4-2/C821A, a ligase-dead mutant of Nedd4-2,
for degradation (Bence, Sampat, & Kopito, 2001; Gong, Radulovic,
or Nedd4-2 knockdown by Nedd4-2-specific siRNA abrogated the
Figueiredo-Pereira, & Cardozo, 2016; Schwartz & Ciechanover, 2009).
stimulatory effect of Sgk2 on OATs, indicating Sgk2 regulated OATs
The UPS has been reported to be involved in modulating OATs via alter-
possibly through Nedd4-2 phosphorylation (H. Wang et al., 2016; D.
ing cellular location and protein stability (Fig. 3).
Xu, Huang, Toh, & You, 2016). Insulin, an endogenous hormone, in-
creased OAT4 transport activity resulting from an increased OAT4
7.3.1. Regulation of OATs by ubiquitination and deubiquitination
cell surface. Furthermore, insulin up-regulated OAT4 through phos-
Ubiquitination is a PTM that conjugates ubiquitin molecules to target
phorylating Nedd4-2 on Ser327, leading to the impaired association
proteins, catalyzed by ubiquitination enzymes, including ubiquitin-
between OAT4 and Nedd4-2. The up-regulation effect was abrogated
activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiq-
by knocking down the endogenous Nedd4-2 by Nedd4-2-specific
uitin ligase (E3). Nedd4-1 and Nedd4-2, the two E3 ubiquitin ligases,
siRNA (H. Wang et al., 2019b). In summary, the dynamic phosphoryla-
have been identified as important regulators for OATs (Fig. 3). Phorbol
tion of Nedd4-2, a central switch, at different sites exerts opposite reg-
12-Myristate 13-Acetate (PMA), a PKC activator, inhibited OAT trans-
ulations of OATs through different modulators, followed by distinct
port activity and expression in cultured cells. Such inhibition resulted
conformational changes of Nedd4-2 and distinct associations between
from an increased OAT ubiquitination, following PKC-promoted interac-
Nedd4-2 and OATs, which leads to the change in OAT transport activ-
tion between OATs and Nedd4-2, which led to an accelerated internali- ity and expression.
zation of OATs from cell surface to early endosomes and subsequent
degradation (S. Li, Zhang, & You, 2013; D. Xu, Wang, & You, 2016a; Q.
7.3. Regulation of OATs by ubiquitin-proteasome system
Zhang, Suh, Pan, & You, 2012). Overexpression of Nedd4-1 or Nedd4-2
decreased the OAT1 protein expression and transport activity following
Ubiquitin, an 8.6 kDa protein, consists of 76 amino acids. The addi-
the enhanced OAT1 ubiquitination in cultured cells. Knocking down
tion of ubiquitin to the lysine residue(s) of a substrate protein is called
endogenous Nedd4-2 with Nedd4-2-specific siRNA or overexpression
ubiquitination, and ubiquitination could occur in different types of con-
of Nedd4-2/C821A, a ligase-dead mutant of Nedd4-2, abrogated the
jugation including monoubiquitination (conjugation of one single ubiq-
PKC-induced change in OAT1 ubiquitination, expression, and transport
uitin to one single lysine on the substrate), multi-ubiquitination
activity in cultured cells. And PKC-dependent changes in OAT1 ubiquiti-
(conjugation of several monoubiquitin molecules to multiple lysine res-
nation, expression, and transport activity were not affected by knocking
idues on the substrate), and polyubiquitination. Ubiquitin itself has
down endogenous Nedd4-1 or overexpression of Nedd4-1/C867S, a
seven lysine residues and an N-terminal methionine residue including
ligase-dead mutant of Nedd4-1, in cultured cells (D. Xu, Wang, Zhang,
K6, K11, K27, K29, K33, K48, K63, and M1, and a polyubiquitin chain is
& You, 2016). In summary, ubiquitin conjugation to OATs, catalyzed
formed between a glycine residue of one ubiquitin molecule and a ly-
by Nedd4-1 or Nedd4-2, triggers the internalization of OATs from
sine residue or N-terminus of another ubiquitin molecule. The addition
plasma membrane to intracellular endosomes and subsequent degrada-
of a polyubiquitin chain to a single lysine residue of the target protein is
tion in proteolytic systems. As a result, the amount of OATs at the cell
called polyubiquitination (Komander & Rape, 2012; Pickart & Eddins,
surface is reduced, and OAT transport activity is subsequently
2004). Ubiquitination regulates the target proteins by affecting their
decreased. Nedd4-1 is mainly involved in the constitutive OAT
ubiquitination, whereas Nedd4-2 is largely involved in PKC-regulated
to a decrease of OAT1 degradation rate (Fig. 3). Therefore, proteasome OAT ubiquitination.
inhibitors can provide a novel tool to reverse the ubiquitination-
Countering the ubiquitination is a process called deubiquitination
induced downregulation of OATs expression and transport activity, in-
that removes ubiquitin molecules from the target proteins by
dicating their potential influence on the renal OATs-mediated drug dis-
deubiquitinating enzymes (DUBs) (Amerik & Hochstrasser, 2004;
position and drug-drug interactions. Besides, other proteasome
Komander, Clague, & Urbe, 2009). Ubiquitination and deubiquitination
inhibitors are currently in clinical trials, and their influences on the kid-
form an opposing network and are related to a variety of physiological
ney OATs could be attentioned.
and pathological processes (Cai, Culley, Zhao, & Zhao, 2018; Lee et al.,
2006; Y. Wu et al., 2018; Zheng et al., 2016).
7.4. Regulation of OATs by SUMOylation and deSUMOylation
To date, approximately 100 human DUBs has been found, and DUBs
can be classified into six families including the ubiquitin-specific prote-
SUMOylation and deSUMOylation, a pair of opposing and dynamic
ases (USPs), the ubiquitin C-terminal hydrolases (UCHs), the Josephin
PTMs, refer to the process, which adds SUMO to or removes SUMO
family, the ovarian tumor proteases (OTUs), Zn-dependent JAB1/MPN/
from lysine residue of the target protein, catalyzed by specific enzymes.
MOV34 metalloprotease DUBs (JAMMs), and the motif interacting
SUMOylation and deSUMOylation create an on and off switch which is
with ubiquitin (MIU)-containing novel DUB family (MINDYs). (Abdul
essential for biological regulations and are involved in various cellular
Rehman et al., 2016; Clague et al., 2013). A variety of membrane pro-
processes in health and disease (Flotho & Melchior, 2013; C. Guo &
teins, such as channels, receptors, and transporters, are regulated Henley, 2014; Zhao, 2007).
through deubiquitination process by DUBs (Butterworth et al., 2007;
Mines, Goodwin, Limbird, Cui, & Fan, 2009; L. Zhang et al., 2012; R.
7.4.1. Regulation of OATs by SUMOylation Zhou et al., 2013).
SUMOylation is another type of post-translational modification
The investigations on the regulation of OATs by DUBs demonstrated
known as a crucial regulatory mechanism of protein function on both
that overexpression of USP8 decreased OAT1 ubiquitination, leading to
nuclear proteins and cellular membrane proteins (Gareau & Lima,
an increased OAT1 expression at the cell surface and an increased
2010; Gill, 2004; Kang, Saunier, Akhurst, & Derynck, 2008; Plant et al.,
OAT1 transporter activity in cultured cells (Fig. 3). No significant differ-
2010; Rajan et al., 2015; Rajan, Plant, Rabin, Butler, & Goldstein, 2005;
ence in OAT1 expression and transport activity was observed in cells
Ulrich, 2005, 2008). Till now three functional isoforms (SUMO1-3)
transfected with an inactive mutant of USP8 as compared to those in
have been identified in mammals, and all three isoforms are expressed
control cells. Furthermore, knocking down the endogenous USP8 in
in a wide range of tissues, such as brain, lung, liver, Pancreas, and kid-
COS-7 cells by USP8-specific siRNA led to an increase in OAT1
ney. SUMO2 and SUMO3 are usually written as SUMO2/3 since they
ubiquitination which correlated with a reduced OAT1 transport activity
share 97% identity in their amino acid sequences, while SUMO2/3 only
(J. Zhang, Liu, & You, 2017).
shares 50% homology with SUMO1. Although SUMO proteins are con-
sidered as the member of the ubiquitin-like protein family, they only
7.3.2. Regulation of OAT transport activity by proteasome inhibitors
share approximately 18% identity with ubiquitin, and all three SUMO
The ubiquitin-proteasome system is the major proteolytic machin-
proteins are polypeptides of ~12 kDa. Like ubiquitination, the conjuga-
ery that degrades the majority of ubiquitinated intracellular proteins
tion of SUMO to target proteins also involves a series of enzymatic
and certain ubiquitinated membrane proteins in eukaryotic cells
steps. The inactive precursors of SUMO proteins are initially processed
(Alam, Farasyn, Crowe, Ding, & Yue, 2017; Jandial et al., 2009; Ogura
by members of the SUMO1/sentrin specific peptidase (SENP) family to
et al., 2011). Cancer cells have enhanced nuclear factor kappa B
truncate a ten amino acid long fragment from the C terminus, therefore
(NF-kB) activity and are dependent on this signaling pathway for cell
exposing a C-terminal diglycine motif to mature the SUMO proteins.
survival and proliferation. Proteasome inhibition can down-regulate
Then the SUMO-activating enzyme (E1) catalyzes the ATP-dependent
NF-kB-dependent gene expression and lead to an arrest of tumor
formation of a thioester bond between the C terminus of matured
growth. Besides, proteasome inhibition can stabilize tumor suppressor
SUMO and the active cysteine residue of a SUMO-activating enzyme
proteins and repress cell cycle progression. As many cancer cells are
(E1). The activated SUMO is later transferred to a SUMO-conjugating
highly sensitive compared with normal cells for proteasome inhibition,
enzyme (E2). Eventually, SUMO is attached to the specific lysine residue
therefore proteasome has become an important drug target for cancer
on the target protein with the facilitation of SUMO protein ligase (E3). A
therapy (Lenos & Vermeulen, 2016; Thibaudeau & Smith, 2019). The
SUMO substrate can be modified by various types of SUMO conjugation:
26S proteasome is comprised of a proteolytic 20S core particle (20S pro-
monoSUMOylation (conjugation of one single SUMO to one single ly-
teasome) and one or two capped 19S regulatory particles for recogniz-
sine on the target protein), multiSUMOylation (conjugation of several
ing the ubiquitinated proteins (Voges, Zwickl, & Baumeister, 1999).
monoSUMO molecules to multiple lysine residues on the target pro-
Bortezomib, carfilzomib, and ixazomib, approved by FDA for the treat-
tein), and polySUMOylation (extended polySUMO chain). Majority of
ment of patients with multiple myeloma, are reversible or irreversible
SUMO substrates contain the consensus motif, Ψ-K-x-D/E (where ψ is
20S proteasome inhibitors with suppression of chymotrypsin-like activ-
a large hydrophobic residue, K is the lysine conjugated to SUMO, x is
ity. The pharmacodynamic study showed carfilzomib significantly
any amino acid, E is a glutamic acid, and D is an aspartic acid). SUMO2
inhibited the 20S proteasome activity in the kidney of Sprague-
and SUMO3 contain internal SUMO consensus motifs, and therefore
Dawley rats (FDA, 2012). As ubiquitination is one essential post-
are capable of forming polySUMO chains, whereas SUMO1 does not
translational modification which mediates the regulation of OATs, the share such property.
alteration of proteasome activity induced by proteasome inhibitors
Recently published work showed that in COS-7 cells, OAT3 transport
can also potentially affect the transporter function.
activity and expression at the plasma membrane were increased by
At clinically therapeutic concentrations, incubation of OAT1-
short term PKA activation. Such increase resulted from the enhanced
expressing HEK293 with bortezomib or carfilzomib led to a significant
rate of OAT3 recycling with no change in the rate of OAT3 internaliza-
accumulation of ubiquitinated OAT1, suggesting that ubiquitinated
tion. In addition, OAT3 was identified as a SUMO substrate, and the con-
OAT1 degraded through proteasomes (Fan, Wang, & You, 2018; Fan &
jugation of SUMO2/3 to OAT3 was also PKA-dependent. PKA activation
You, 2020). Bortezomib and carfilzomib significantly stimulated trans-
enhanced OAT3 SUMOylation, and such enhancement can be abrogated
port activity, and there was a positive correlation between the degree
by the presence of PKA-specific inhibitor H-89 (Fig. 4) (H. Wang, Zhang,
of proteasomal inhibition by bortezomib and augmentation of OAT1
& You, 2019a). In Oat3 knockout mice, bile acids such as cholic acid and
transporter activity. Bortezomib- and carfilzomib-induced increase in
taurocholic acid accumulated. Both substances are endogenous sub-
OAT1 surface expression and transport activity were mainly attributed
strates of Oat3 and can activate G protein-coupled receptors (GPCRs)
Fig. 4. Regulation of OATs by SUMOylation and deSUMOylation enzyme Senp2. S: SUMO, Senp2: SUMO1/sentrin specific peptidase 2, PKA: Protein kinase A.
(Deutschmann et al., 2018; Duboc, Tache, & Hofmann, 2014). The acti-
SUMOylation, which paralleled well with an increased OAT3 expression
vation of GPCRs elevated the cAMP level leading to PKA signaling path-
and transport activity. Coimmunoprecipitation experiments revealed
way activation. PKA enhanced OAT3 SUMOylation, recycling rate, and
that Senp2 directly interacted with OAT3/Oat3 both in COS-7 cells and
transport activity. Thus, the accumulation of bile acids contributed by
in rat kidneys (Fig. 4) (Wang & You, 2019).
OAT3 reduction could potentially result in the upregulation of OAT3 ex-
Senps have been reported as key regulators in upholding a balance
pression and function to form a negative feedback loop. This connection
between SUMOylated and unSUMOylated proteins that are crucial for
between OAT endogenous substrates and PTMs of OATs is an interesting
physiological homeostasis. Many investigations indicated the alter-
area to explore. We now know OAT3 is the substrate of SUMOylation.
ations in the amount of Senps under pathophysiological conditions,
However, which lysine residues on OAT3 are responsible for SUMO2/3
and Senps were associated with the progress of a number of diseases,
conjugation is still unknown. Further investigations of mapping the
especially cancer. For example, the level of Senp2 was decreased in
SUMO conjugation sites on OAT3 is needed.
bladder cancer and hepatocellular carcinoma (HCC) tissues, and the
hyperexpression of Senp2 resulted in the suppressions on both bladder
cancer metastasis and HCC development (Shen, Zhu, Yang, & Ji, 2012;
7.4.2. Regulation of OATs by deSUMOylation
Tan et al., 2017). Other than cancers, the overexpression of Senp2
SUMOylation is a dynamic and reversible event, and SUMO is re-
played an important role in the development of congenital heart defects
moved from target protein by SUMO-specific proteases including mem-
and cardiac dysfunction by enhancing deSUMOylation (Kim et al.,
bers of ubiquitin-like specific protease (Ulp, in yeast) and SENP family
2012). Thus, Senps have received increasing recognition as interesting
(in mammals) (Han, Feng, Gu, Li, & Chen, 2018; Hannoun,
targets for drug discovery. 1,2,5-Oxadiazoles were developed as a new
Greenhough, Jaffray, Hay, & Hay, 2010; Miura & Hasegawa, 2010;
class of Senp2 inhibitors, which could have the therapeutic potential
Ulrich, 2005). So far, six human Senp proteins have been isolated and
for many diseases (Kumar, Ito, Takemoto, Yoshida, & Zhang, 2014). Fur-
shown to have the ability to de-conjugate SUMO. Among them (Yeh,
ther studies exploring the effects of Senp2 inhibitors on OAT transport
2009), Senp2 is identified to travel between the nucleus and the cyto-
activity, surface expression, and SUMOylation would be very exciting.
plasm, modulating the activities of some plasma membrane proteins in-
cluding receptors, channels, and transporters (Benson et al., 2007;
Itahana, Yeh, & Zhang, 2006; Qi et al., 2014; Tan et al., 2017).
7.5. Regulation of OATs by Glycosylation
It was recently revealed that in COS-7 cells, overexpression of Senp2,
a member of the SENP family, resulted in a decreased OAT3
Glycosylation, a common and complex PTM of proteins, is the cova-
SUMOylation, which paralleled well with a reduced OAT3 expression
lent attachment of carbohydrates to specific residues of a target protein,
and transport activity. Furthermore, knocking down the endogenous
which expands the proteasome complexity and modulates the target
Senp2 with Senp2-specific siRNA led to an enhanced OAT3
protein via changes in cellular location, protein stability, protein
structure, and protein activity (Eichler, 2019). Glycosylation are classi-
Kolch, & Kholodenko, 2013; Rajan et al., 2015; Yang, Jaffray,
fied into several different protein-sugar linkages, such as N-
Senthinathan, Hay, & Sharrocks, 2003). It would be interesting to ex-
glycosylation, O-glycosylation, C-glycosylation, S-glycosylation, and P-
plore new potential crosstalk among various PTMs of OATs.
glycosylation. N-glycosylation and O-glycosylation are predominantly
found in eukaryotes, and N-glycosylation accounts for more than half
7.7. Remote Sensing and Signaling Hypothesis of OATs
of the protein glycosylation in eukaryotes. N-glycosylation refers to
the attachment of a glycan to the asparagine residue of the target pro-
In the recent years, systems biology studies together with the in-
tein within a consensus peptide sequence (Asn-X-Ser/Thr, X can be
vestigations of OAT knockout mice have indicated that the roles of
any amino acid except proline). For membrane proteins, endoplasmic-
OATs in different organs may form a network, and this network
Golgi pathway, glycosidases, and glycosyltransferases are involved in
allows the intercellular and inter-organ communication. Such com-
the glycosylation process (Christiansen et al., 2014). Many membrane
munication between cells, as well as between organs, regulates the
proteins have been identified as the substrates of glycosylation, and gly-
local and whole-body homeostasis. This hypothesis is called remote
cosylation plays a critical role in regulating the function and activity of
sensing and signaling (Ahn & Nigam, 2009; S. K. Nigam, 2018; S. K.
those membrane proteins (L. B. Li et al., 2004). Nigam et al., 2015).
OAT1 has been reported as the substrate of glycosylation. Asp-39 on
The overlapping of substrate specificities among different OAT iso-
OAT1/Oat1 is crucial for substrate recognition of glycosylation, and gly-
forms, the wide tissue distributions of different OAT isoforms
cosylation is essential for the targeting of OAT1/Oat1 onto the plasma
(e.g., kidney, liver, brain, placenta, retina, olfactory mucosa, etc.), and
membrane (Tanaka, Xu, Zhou, & You, 2004). Furthermore, mutagenesis
the various regulations of OAT expression and function mediated by
of glycosylation sites on OAT4 and treatment of tunicamycin, a glycosyl-
signaling molecules secreted from remote tissues into the body fluid
ation inhibitor, resulted in a non-glycosylated OAT4 and the failure of
contribute to the complicated communication network of OATs
targeting OAT4 onto the plasma membrane in cultured cells. In addition,
(Burckhardt, 2012; Roth, Obaidat, & Hagenbuch, 2012; You, 2002). For
OAT4 expressed in CHO-Lec1 cells, carrying oligosaccharides bearing
example, it was reported that indoxyl sulfate, a gut microbiome-
mannose-rich intermediates, had reduced binding affinity towards the
derived metabolite and endogenous OAT substrate, up-regulated OAT1
substrates compared with OAT4 in CHO wild-type cells, and it was con-
via AhR and EGFR signaling under the control of miR-223 in cultured
cluded that processing of added oligosaccharides from mannose-rich
cells, and the up-regulation on OAT1/Oat1 was to react to the elevated
type to complex type was important for modulating OAT4 substrate
indoxyl sulfate level and to maintain homeostasis through inducing
binding affinity (F. Zhou et al., 2005). Congenital disorders of glycosyla-
renal secretion. This phenomenon was observed in cultured cells, rat
tion (CDG), an ever-expanding disease, are a group of inherited meta-
kidneys, and human kidneys (Jansen et al., 2019). Oat3 was involved
bolic disorders, which affecting glycosylation process. As many steps
in the regulation of blood pressure through the remote sensing and sig-
and enzymes are involved in the glycosylation process, CDG patients
naling. The blood pressure of Oat3 knockout mice was 15% lower than
commonly are deficient of one or more enzymes for one or more glyco-
that of control mice. Metabolomic analysis indicated that plasma con-
sylation steps and show variable clinical symptoms including multi-
centrations of Oat3 substrates were increased in Oat3 knockout mice,
organ dysfunction (Bryant et al., 2020; Ferreira et al., 2018). Kidney dis-
and some endogenous Oat3 substrates could serve as vasodilators, such
function, nephropathy, and lesion of proximal tubule, where OATs are
as thymidine, cAMP, and cGMP, to reduce the blood pressure (Vallon
mainly expressed, are symptoms of CDG, and glycosylation is critical
et al., 2008; Vallon, Eraly, et al., 2008). In addition, the renal excretion
for modulating transport activity of OATs. Thus, OAT function and ex-
of vasodilators, the substrates of Oat3, was reduced responding to the el-
pression in CDG patients would be interesting and exciting to
evated blood pressure, caused by internally and externally environmen- investigate.
tal changes. And then the accumulated vasodilators subsequently
decreased the blood pressure thereby maintaining homeostasis (Ahn &
7.6. Crosstalk between various PTMs Nigam, 2009; Eraly, 2008).
Hormones and growth factors produced and released from the orig-
During the past decade, evidence for comprehensive crosstalk be-
inal organ under the internal and external stimuli arrive at the target
tween different PTM types has stacked up, especially the interplay
organ and regulate the OATs in the target organ through binding to
between the PTMs occurring on the same type of amino acid residue
the receptors and activating the downstream signaling pathways. For
(s). One of the examples is the crosstalk between ubiquitination and
example, Oat3 expression and transport activity were impaired in the
SUMOylation, in which both ubiquitin and SUMO covalently conjugate
streptozotocin-induced type 1 diabetic rats compared with those in
to the lysine residue (s) of a substrate protein. One scenario is that ubiq-
wild-type rats, and insulin treatment abolished the effects.
uitin and SUMO modify the same lysine residue(s) in a target protein
Streptozotocin was used to damage insulin-producing beta cells in the
through competitive manner. On the other hand, SUMO and ubiquitin
pancreas to induce diabetes in animal models. Protein kinase C alpha
may modify different lysine residues in a substrate protein. In such
(PKCα) and phospho-PKCα expression were increased in diabetic rats,
case conjugation of SUMO may potentially mask a nearby ubiquitin con-
and insulin treatment reversed the effects (Phatchawan et al., 2014).
jugation site. Under both circumstances, SUMOylation may preclude the
In addition, insulin stimulated OAT4 expression and transport activity
ubiquitin-mediated degradation of target protein (Hunter & Sun, 2008).
through impairing the interaction between Nedd4-2 and OAT4, and
It was demonstrated that the enhancement of OAT3 SUMOylation by
Nedd4-2 knockdown abolished the stimulation effect of insulin on
PKA activation paralleled with a decrease in OAT3 ubiquitination in cul-
OAT4 in cultured cells (H. Wang et al., 2019b). IGF-1, produced in the
tured cells. Therefore, SUMOylation and ubiquitination may coordi-
liver under stimuli, up-regulated renal OAT3 function through PKA fol-
nately regulate OAT3 through crosstalk (H. Wang et al., 2019a).
lowing binding to its receptor in cultured cells, which was abrogated
Other PTMs, which also occur on lysine residue(s) of the target pro-
by PKA inhibitor H89 and linsitinib (J. Zhang et al., 2020). Besides, it
tein, could potentially be involved in the crosstalk with both
was demonstrated that Angiotensin II, produced in adrenal gland, re-
ubiquitination and SUMOylation. Besides the direct competitions on
duced OAT1 and OAT3 function through PKC in cultured kidney cells
the same lysine residue(s) among these modifications, underlying
(P. Duan et al., 2010; S. Li et al., 2009). Furthermore, parathyroid Hor-
mechanism can be more complex and may not follow a uniform rule
mone, produced in parathyroid glands in the neck, enhanced OAT4 ac-
(Appikonda et al., 2018; Caron, Boyault, & Khochbin, 2005; Gareau &
tivity through a PKA independent pathway in cultured kidney cells (P.
Lima, 2010). In addition, the interplay could also happen between two
Duan, Li, & You, 2012). In remote sensing and signaling model, OATs
or more PTMs modifying different types of amino acid residues
play an essential role in intercellular and inter-organ communication
(Hietakangas et al., 2003; Muller, Matunis, & Dejean, 1998; Nguyen,
and in maintaining local and whole-body homeostasis. Such complex
and dedicated communication is carried out by hormones, small mole-
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Declaration of Competing Interest
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& Slitt, A. L. (2008). Drug-metabolizing enzyme and transporter expression in a
The authors declare that there are no conflicts of interest.
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