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Mutations in renal drug efflux transporter hOATv1 cause hyperuricemia

Hyperuricemia, traditionally linked to gout, has recently been implicated in cardiovascular diseases and hypertension. One of the major determinants of plasma urate concentration is renal excretion that is dependent on the balance between reabsorption and secretion. Previously we identified that renal urate absorption is mainly performed by apical urate/anion exchanger, URAT1/SLC22A12, and basolateral voltage‐driven urate efflux transporter, URATv1/SLC2A9 in tandem in proximal tubular cells. In contrast, the molecular mechanism of renal urate secretion remains elusive. Here, we report that newly characterized human renal voltage‐driven drug efflux transporter, hOATv1 also functions as a long‐hypothesized urate exit pathway at the apical side of renal proximal tubules that determines the direction of net urate flux. Loop diuretics such as furosemide and bumetanide substantially interacted with hOATv1, providing the first molecular evidence for loop diuretics‐induced hyperuricemia. The in vivo role of hOATv1 is supported by the fact that missense mutations in this transporter found in hyperuricemia patients with urate underexcretion abolished urate efflux capacity in vitro. Our results demonstrate that hOATv1 is component of renal urate secretory pathway involved in the formation of both in primary and secondary hyperuricemia.