Genomic Structure and in Vivo Expression of the Human Organic Anion Transporter 1 (hOAT1) Gene

Bahn, Andrew; Prawitt, Dirk; Buttler, Diana; Reid, Glen; Enklaar, Thorsten; Wolff, Natascha A.; Ebbinghaus, Christian; Hillemann, Annette; Schulten, Hans-Juergen; Gunawan, Bastian; Füzesi, L.; Zabel, Bernhard; Burckhardt, Gerhard

doi:10.1006/bbrc.2000.3230

Cited by 50 publications

(35 citation statements)

References 32 publications

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“…Research thus far has focused largely on MATE2K since it was identified several years before the functionality of MATE2 was determined. In addition, variants of OAT1 have been identified (OAT1-1, OAT1-2, OAT1-3, OAT1-4); however, preliminary reports suggest that only OAT1-1 and OAT1-2 are functional (88,89). Three splice variants of OAT3 have been identified, but whether they are translated into functional proteins is unknown because transporter function has not been evaluated (90).…”

Section: Alternative Splicing Of Renal Secretory Transportersmentioning

confidence: 99%

Renal Transporters in Drug Development

Morrissey

Stocker

Wittwer

et al. 2013

Annu. Rev. Pharmacol. Toxicol.

280

277

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The kidney plays a vital role in the body's defense against potentially toxic xenobiotics and metabolic waste products through elimination pathways. In particular, secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotics, including many prescription drugs. In the past decade, considerable progress has been made in understanding the impact of renal transporters on the disposition of many clinically used drugs. In addition, renal transporters have been implicated as sites for numerous clinically important drug-drug interactions. This review begins with a description of renal drug handling and presents relevant equations for the calculation of renal clearance, including filtration and secretory clearance. In addition, data on the localization, expression, substrates, and inhibitors of renal drug transporters are tabulated. The recent US Food and Drug Administration drug-drug interaction draft guidance as it pertains to the study of renal drug transporters is presented. Renal drug elimination in special populations and transporter splicing variants are also described.

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Section: Alternative Splicing Of Renal Secretory Transportersmentioning

confidence: 99%

Renal Transporters in Drug Development

Morrissey

Stocker

Wittwer

et al. 2013

Annu. Rev. Pharmacol. Toxicol.

280

277

View full text Add to dashboard Cite

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“…Subsequently, these lineages expanded through independent tandem duplications to produce multiple gene pairs (17,18). For human OAT1, four splice variants, i.e., OAT1-1 to OAT1-4, exist, whereas individual roles of these variants are not known (3,23).…”

Section: Genomic Organization and Possible Transcriptional Regulationmentioning

confidence: 99%

Molecular physiology of renal organic anion transporters

Sekine¹,

Miyazaki²,

Endou³

2006

American Journal of Physiology-Renal Physiology

216

167

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Recent advances in molecular biology have identified three organic anion transporter families: the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC. These families play critical roles in the transepithelial transport of organic anions in the kidneys as well as in other tissues such as the liver and brain. Among these families, the OAT family plays the central role in renal organic anion transport. Knowledge of these three families at the molecular level, such as substrate selectivity, tissue distribution, and gene localization, is rapidly increasing. In this review, we will give an overview of molecular information on renal organic anion transporters and describe recent topics such as the regulatory mechanisms and molecular physiology of urate transport. We will also discuss the physiological roles of each organic anion transporter in the light of the transepithelial transport of organic anions in the kidneys.OAT; urate; organic anion transporting peptide; multidrug resistance-associated protein THE ORGANIC ANION (OA) transport system has been a major subject in renal physiology over the past 100 years, because this system represents the tubular secretory pathway. OAs include numerous substances of both endogenous and exogenous origins, and the renal OA transport system plays a pivotal role in the elimination of potentially toxic compounds including metabolites, xenobiotics, and drugs. Because of its complexity, there are still limitations in a detailed analysis of the renal OA transport system by physiological techniques. A notable advance was made in the 1990s by the identification of three major organic anion transporter families: the OAT (organic anion transporter) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLCO, and the multidrug resistance-associated protein (MRP) family encoded by ABCC (ATP-binding cassette) superfamily. The identification of each transporter enabled us to perform precise functional analyses of the system. Molecular knowledge in this area has rapidly increased, and various information has appeared within the last few years. In this review, first, we will give an overview of molecular information on OA transporters. Then, we will focus on recent advances, particularly those in the study of the OAT family, which represents the major and classic renal OA transport system. With regard to the OATP and MRP families, we will touch only potentially important points in renal physiology. The major topics described in this paper are as follows: 1) regulatory mechanisms of OA transporters, such as gender differences, intracellular signaling, genomic organization, pathophysiological states and scaffolding proteines; 2) molecular physiology of the renal urate transporter; and 3) organization of transepithelial transport of organic anions. For historical and physiological backgrounds on renal OA...

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“…Only recently, the homologous protein was cloned from human kidney and was called hOAT1 (13) or hPAHT (28,34). The genomic DNA from human hOAT1 is organized into 10 exons, and 4 isoforms have been described (2). Furthermore, it has been shown that OAT1 represents the basolateral, polyspecific transporter for organic anions (45), which had been functionally described for some time (38).…”

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confidence: 99%

Action of EGF and PGE₂on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells

Sauvant

Hesse

Holzinger

et al. 2004

American Journal of Physiology-Renal Physiology

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. Action of EGF and PGE2 on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells. Am J Physiol Renal Physiol 286: F774-F783, 2004. First published November 25, 2003 10.1152/ajprenal.00326.2003We recently showed that, in a proximal tubule cell line (opossum kidney cells), epithelial growth factor (EGF) stimulates basolateral organic anion transport (OAT) via ERK1/2, arachidonic acid, phospholipase A 2, and generation of prostaglandins. PGE2 binds the prostanoid receptor and, thus, activates adenylate cyclase and PKA, which stimulate basolateral organic anion uptake. In the present study, we investigated whether this regulatory cascade is also true 1) for ex vivo conditions in isolated renal proximal (S2) tubules from rabbit and 2) in a human renal epithelial cell line stably expressing human OAT1 (IHKE-hOAT1). EGF activated ERK1/2 in S2 tubules and IHKE-hOAT1, and, in both cases, inhibition of ERK activation (by U-0126) abolished this stimulation. In S2 tubules and IHKE-hOAT1, EGF led to an increase of organic anion uptake, which again was inhibited by U-0126. PGE 2 stimulated basolateral organic anion uptake in rabbit S2 tubules and IHKEhOAT1. EGF-and PGE 2-mediated stimulation of organic anion uptake was abolished by inhibition of PKA in rabbit S2 tubules and IHKE-hOAT1, respectively. We conclude that 1) stimulation of basolateral organic anion uptake by EGF or PGE 2 is a widespread (if not general) regulatory mechanism, 2) the signal transduction pathway involved seems to be general, 3) stimulation of basolateral organic anion uptake by EGF or PGE 2 is also present under ex vivo conditions and, thus, is not a cell culture artifact, 4) activation of OAT1 is sufficient to explain the stimulatory effects of EGF and PGE 2 in opossum kidney cells and rabbit S2 segments, and 5) stimulation of basolateral OAT1 by EGF or PGE 2 is also important in humans and, thus, may have clinical implications. basolateral transport; epithelial growth factor; extracellular signalregulated kinase 1/2; rabbit isolated proximal tubule; mitogen-activated protein kinase; mitogen-activated protein kinase kinase; IHKE cells; organic anion transport; phospholipase A 2; prostaglandin E2; protein kinase A; regulation THE ORGANIC ANION TRANSPORT (OAT) system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds (37,56). This system consists of organic anion exchanger(s) located at the basolateral membrane and a less well-characterized transport step at the apical membrane (18).The classical basolateral organic anion exchanger is the terminal step in a tertiary active transport system that is dependent on an inward-directed Na ϩ gradient to drive the uptake of ␣-ketoglutarate (␣-KG), which is then exchanged for organic anions (17,23,38,55). The basolateral exchanger for organic anions and dicarboxylates was cloned by three independent groups (46, 51, 58) in 1997 and named OAT1 (rat), ROAT1 (rat), and fROAT1 (winter flounde...

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Genomic Structure and in Vivo Expression of the Human Organic Anion Transporter 1 (hOAT1) Gene

Cited by 50 publications

References 32 publications

Renal Transporters in Drug Development

Renal Transporters in Drug Development

Molecular physiology of renal organic anion transporters

Action of EGF and PGE₂on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells

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Genomic Structure and in Vivo Expression of the Human Organic Anion Transporter 1 (hOAT1) Gene

Cited by 50 publications

References 32 publications

Renal Transporters in Drug Development

Renal Transporters in Drug Development

Molecular physiology of renal organic anion transporters

Action of EGF and PGE2on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells

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Product

Resources

About

Action of EGF and PGE₂on basolateral organic anion uptake in rabbit proximal renal tubules and hOAT1 expressed in human kidney epithelial cells