title: Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules.
abstract: Human organic anion transporter OAT4 is expressed in the kidney and placenta and mediates high-affinity transport of estrone-3-sulfate (E1S). Because a previous study demonstrated no trans-stimulatory effects by E1S, the mode of organic anion transport via OAT4 remains still unclear. In the present study, we examined the driving force of OAT4 using mouse proximal tubular cells stably expressing OAT4 (S2 OAT4). OAT4-mediated E1S uptake was inhibited by glutarate (GA) (IC50:1.25 mM) and [14C]GA uptake via S2 OAT4 was significantly trans-stimulated by unlabeled GA (5 mM) (P<0.001). [3H]E1S uptake via S2 OAT4 was significantly trans-stimulated by preloaded GA (P<0.001) and its [14C]GA efflux was significantly trans-stimulated by unlabeled E1S in the medium (P<0.05). In addition, both the uptake and efflux of [14C]p-aminohippuric acid (PAH) and [14C]GA via S2 OAT4 were significantly trans-stimulated by unlabeled GA or PAH. The immunoreactivities of OAT4 were observed in the apical membrane of proximal tubules along with those of basolateral organic anion/dicarboxylate exchangers such as hOAT1 and hOAT3 in the same tubular population. These results indicate that OAT4 is an apical organic anion/dicarboxylate exchanger and mainly functions as an apical pathway for the reabsorption of some organic anions in renal proximal tubules driven by an outwardly directed dicarboxylate gradient.
authors.affiliation: Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
authors.forename: Sophapun
authors.initials: S
authors.lastname: Ekaratanawong
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.forename: Hiroki
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Rie
authors.initials: R
authors.lastname: Noshiro
authors.forename: Michio
authors.initials: M
authors.lastname: Takeda
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Samaisukh
authors.initials: S
authors.lastname: Sophasan
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D029382:Dicarboxylic Acid Transporters / Q000737:chemistry / Q000502:physiology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014316:Tritium; D015854:Up-Regulation; D010130:p-Aminohippuric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002250:Carbon Radioisotopes; D029382:Dicarboxylic Acid Transporters; D005977:Glutarates; D027381:Liver-Specific Organic Anion Transporter 1; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C498886:SLC22A9 protein, human; C498887:Slco1b2 protein, mouse; C114338:organic anion transport protein 3; D014316:Tritium; D004970:Estrone; C017296:estrone sulfate; D010130:p-Aminohippuric Acid