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Articles in PresS, published online ahead of print December 17, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00405.2002
Submitted on November 13, 2002
Accepted on December 15, 2002
1 Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC, USA
2 Laboratory of Pharmacology and Chemistry, NIEHS/National Institutes of Health, Research Triangle Park, NC, USA
* To whom correspondence should be addressed. E-mail: pritcha3{at}niehs.nih.gov.
Basolateral uptake of organic anions in renal proximal tubule cells is indirectly coupled to the Na+ gradient through Na+/dicarboxylate cotransport and organic anion/dicarboxylate exchange. One member of the organic anion transporter (OAT) family, Oat1, is expressed in proximal tubule and is an organic anion/dicarboxylate exchanger. However, a second organic anion carrier, Oat3, is also highly expressed in renal proximal tubule, but its mechanism is unclear. Thus, we have assessed Oat3 function in Xenopus oocytes and rat renal cortical slices. Probenecid-sensitive uptake of para-aminohippurate (PAH, a substrate for both Oat1 and Oat3) and estrone sulfate (ES, an Oat3 substrate) in rat Oat3-expressing oocytes was significantly trans-stimulated by preloading the oocytes with the dicarboxylate, glutarate (GA). GA stimulation of ES transport by oocytes co-expressing rabbit sodium dicarboxylate cotransporter 1 and rOat3 was significantly inhibited when the preloading medium contained lithium or methylsuccinate, or when Na+ was absent. All these treatments inhibit the sodium dicarboxylate cotransporter, not rOat3. Lithium, methylsuccinate, and Na+ removal had no effect when applied during the ES uptake step, rather than during the GA preloading step. Concentrative ES uptake in rat renal cortical slices was also demonstrated to be probenecid- and Na+-sensitive. Accumulation of ES was stimulated by GA and this stimulation was completely blocked by probenecid, lithium, methylsuccinate, taurocholate, and removal of Na+. Thus, Oat3 functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the Na+ gradient.
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