Molecular mechanisms of urate transport in renal tubules: localization and function of urate transporters

Urate, a naturally occurring product of purine metabolism, is present at higher levels in human blood than in other mammals, because humans have an effective renal urate reabsorption system in addition to their evolutionary loss of hepatic uricase by mutational silencing. The urate transporter URAT1 encoded by SLC22A12 is a urate anion exchanger regulating blood urate levels. URAT1 is localized in the apical membrane of renal proximal tubules and targeted by uricosuric and antiuricosuric agents. Idiopathic renal hypouricemia is due to the genetic defect of SLC22A12. Recently it has been shown that the proximal tubule apical membrane organic anion transporter OAT4 transports urate at low affinity and responsible for the hyperuricemia cased by thiazide diuretics. Transport of urate via URAT1 is driven by the intracellular lactate that is accumulated by Na+/lactate cotransporter slc5a8 and slc5a12. URAT1 is proposed to be involved in the multimolecular complex "transportsome" that allows the cooperation of multiple transporters.