Abstract
The kidney plays a dominant role in urate elimination ; it excretes approximately 70% of the daily urate production. It was postulated that decreased renal urate clearance leads to hyperuricemia in most hyperuricemic patients. Thus, it is important to understand the mechanism of renal urate handling mediated by renal urate transporters. Recently, we identified that a member of the sugar transport facilitator family, SLC2A9, functions as an efflux transporter of urate from the tubular cell. We suggested be renamed URATv1 (voltage-driven urate transporter). The in vivo role of URATv1 is supported by the fact that a renal hypouricemia patient without any mutations in SLC22A12 (URAT1) demonstrated a missense mutation in SLC2A9, which reduced urate transport activity in vitro. Given its predominantly basolateral membrane localization in proximal tubular cells, we propose that GLUT9 is responsible for transferring urate from the cell to the peritubular interstitium as a second step in reabsorption, following the initial step mediated by URAT1. Because URATv1 seems to be a promising therapeutic target for hyperuricemia, we further investigated the urate transport properties of URATv1 in this study. The alteration of intracellular pH affects URATv1-mediated urate uptake. K+ replacement from Na+ and gluconate replacement from Cl- reduced URATv1-mediated urate efflux.
Benzbromarone and indomethacin strongly, inhibited URATv1-mediated urate uptake, but probenecid caused only week inhibition. These findings indicate that URATv1 has different urate transport properties from URAT1 and suggested that it can be a promising therapeutic target for hyperuricemia.
