Functional characterization of a novel urate efflux transporter URATv1 (SLC2A9) and its relation to renal hypouricemia.

Abstract

Reanl urate handling is clinically important because underexcretion of urate causes hyperuricemia. In 2002, we identified an apical urate‐anion exchanger, URAT1 encoded by SLC22A12. But it is currently not known how urate taken up via URAT1 exits from the tubular cell. In this study, we functionally characterized SLC2A9 gene product GLUT9 in search of urate excreting transporter. GLUT9 expressed Xenopus oocytes transported [14C]urate time‐ and concentration‐dependent manner (Km, 365 µM). Interestingly, we found that its transport was Na+‐independent and enhanced at high concentrations of extracellular potassium, indicating that GLUT9‐mediated urate transport is affected by the changes in membrane potential. GLUT9‐expressing oocytes preloaded with radiolabelled urate showed a time‐dependent efflux of radioactivity in the standard uptake solution Thus, we renamed this novel urate transporter as voltage‐driven urate transporter (URATv1). In vivo role of URATv1 is supported by the fact that a renal hypouricemia patient without any mutations in SLC22A12 was found to have a missense mutation P412R in SLC2A9, which reduced urate transport activity in vitro. Considering its basolateral expression in proximal tubules in human kidney, URATv1 is proposed to be a basolateral exit pathway of urate, which is likely to act in tandem with URAT1 for urate reabsorption.