Human Organic Anion Transporter 4 Is a Renal Apical Organic Anion/Dicarboxylate Exchanger in the Proximal Tubules

Abstract

Abstract. Human organic anion transporter OAT4 is expressed in the kidney and placenta and mediates high-affinity transport of estrone-3-sulfate (E 1 S). Because a previous study demonstrated no trans-stimulatory effects by E 1 S, 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 (S 2 OAT4). OAT4-mediated E 1 S uptake was inhibited by glutarate (GA) (IC 50 : 1.25 mM) and [14 C]GA uptake via S 2 OAT4 was significantly trans-stimulated by unlabeled GA (5 mM) (P<0.001).[3 H]E 1 S uptake via S 2 OAT4 was significantly trans-stimulated by preloaded GA (P<0.001) and its [ 14 C]GA efflux was significantly trans-stimulated by unlabeled E 1 S in the medium (P<0.05). In additon, both the uptake and efflux of [14 C]p-aminohippuric acid (PAH) and [14 C]GA via S 2 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.

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

“…Further assessment of OAT4 revealed that it was able to be transstimulated by dicarboxylates [74]. The transstimulation occurred in both directions, suggesting that OAT4 is a bidirectional exchanger [74]. These data indicated that OAT4 exhibits energetics mimicking that of the basolateral organic anion transporters (Oat1 and Oat3).…”

“…Apical expression of OAT4 was then confirmed in renal proximal tubules [73]. Further assessment of OAT4 revealed that it was able to be transstimulated by dicarboxylates [74]. The transstimulation occurred in both directions, suggesting that OAT4 is a bidirectional exchanger [74].…”

“…However, this property of OAT4 does not definitively preclude apical expression. That is, it has been proposed that OAT4 can mediate reabsorption of substrates from the lumen in exchange for dicarboxylates such as a-ketoglutarate [74]. If this apical dicarboxylate exchange is indeed OAT4's principal driving force, a major question arises.…”

Uric acid transport and disease

“…OAT4 (encoded by the SLC22A11 gene) is a multispecific anion transporter present in the apical membrane of epithelial cells from the proximal tubule (57,58). It is involved in luminal urate reabsorption by a mechanism that is transactivated by intracellular dicarboxylates but not by the antiuricosuric agents; it is also affected by the diuretic hydrochlorothiazide (59).…”

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

“…[22][23][24][25][26][27][28][29][30] OAT4 is an apical organic anion/dicarboxylate exchanger, which mainly functions under physiological conditions as an apical pathway for the reabsorption of some organic anions from urine into tubular cells, driven by an outwardly directed dicarboxylate gradient, probably with coupling to apical organic efflux transporters, such as MRP2, NPT1 and, possibly, the human homologue of OATv1. 25 NPT1 expressed in Xenopus laevis oocytes transports estradiol-17β-glucuronide, PAH, benzylpenicillin, faropenem, indomethacin and uric acid and an has affinity for several organic anions, including 2-ketoglutaric acid, β-lactam antibiotics (ampicillin, cefazolin, cephalexin), benzoic acid, lactic acid, probenecid and phenol red.…”