Urate is a metabolite of the purine metabolism. Species differences concerning the handling of urate by the kidneys are well known, leading to the classification of urate secretors showing a fractional excretion for urate (FEurate ) > 1 (pig, rabbit), and urate reabsorbers (human, rat and dog) with FEurate down to 0.1. Several organic anion transporters such as URAT1, OAT1, OAT3, NPT1, UAT or MRP4 are discussed to be involved in renal urate homeostasis. The question arises, which urate transporters are responsible for these species differences.

OAT4 is a human-specific transporter and expressed at the luminal membrane of proximal tubule cells. It is genomically paired with URAT1, a urate/lactate exchanger only present in urate reabsorbers. OAT4 transports urate at plasma-equivalent concentrations, consistent with a second reabsorbing mechanism in humans. We also identified ORCTL3 (SLC22A13) as an apical urate transporter. Sequence analysis revealed that ORCTL3 is only present in reabsorbers, indicating that URAT1 and ORCTL3 define the urate transport direction for reabsorbers. OAT2, which was localized at the basolateral membrane in man and in secretors (pig and rabbit) and at the apical membrane in reabsorbers (rat and mouse), shows substantial uptake of urate. We conclude that OAT2, OAT4 and ORCTL3 are urate transporters, which define, due to their species-specific expression and membrane localization, the classification of urate reabsorbers and secretors.