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 additon, 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.