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Received for publication April 27, 2005.
Revised July 26, 2005.
Accepted for publication August 1, 2005.
A novel member of the organic anion transporter (OAT) family, Oat5 (Slc22a19), has been reported to transport a naturally occurring mycotoxin, ochratoxin A (OTA). However, neither its endogenous substrate and driving force nor physiological functions have been determined. Here, we report the functional characterization of rat Oat5 (rOat5), as well as its intrarenal distribution and membrane localization. When expressed in Xenopus oocytes, rOat5 mediated the transport of sulfate conjugates of steroids such as estrone-3-sulfate (E1S; Km = 18.9 ± 3.9 µM) and dehydroepiandrosterone sulfate (Km = 2.3 ± 0.2 µM) in a sodium-independent manner, in addition to OTA. The rOat5-mediated E1S transport was strongly inhibited by four-carbon (C4) dicarboxylate succinate and longer dicarboxylates (C7-C9). The uptake of [3H]E1S via rOat5 was significantly trans-stimulated by succinate and the efflux of [14C]succinate was significantly trans-stimulated by E1S. A similar trans-stimulatory effect of preloaded succinate on E1S uptake was also detected in cells stably expressing rOat5 (S2 rOat5). rOat5 interacted with chemically heterogenous anionic compounds. The rOat5-mediated E1S transport was inhibited by several sulfate conjugates, such as 4-methylumbelliferyl sulfate and 
-estradiol sulfate, but not by glucuronide conjugates. An immunohistochemical study showed that rOat5 was localized at the apical membrane of renal proximal tubules in the corticomedullary region. rOat5 mRNA was expressed in the late segments (S2 and S3) of proximal tubules. These results indicate that rOat5 is renal organic anion/dicarboxylates exchanger and, under physiological conditions, may function as an apical reabsorptive pathway for organic anions in proximal tubules driven by an outward gradient of dicarboxylates.
Key words:
dicarboxylates, organic anion transporter, organic anions, proximal tubules, steroid sulfates, succinate
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