Human Organic Anion Transporter 3 (hOAT3) can Operate as an Exchanger and Mediate Secretory Urate Flux

Abstract

Background/Aims: Renal secretion of organic anions is critically dependent on their basolateral uptake against the electrochemical gradient. Due to their localization, two transporters are likely involved, namely OAT1 and OAT3. While OAT1 as an exchanger clearly operates in the secretory direction, OAT3 in its previously supposed mode as a uniporter should move anionic substrates from cell to blood. It would thus dissipate gradients established by OAT1 of common OAT1/OAT3 substrates. In the present study we therefore reinvestigated the driving forces of human OAT3. Methods: The human OAT3 obtained from the Resource Center/Primary Database was made functional by site-directed mutagenesis. Using the Xenopus laevis oocyte expression system, hOAT3-mediated transport of estrone sulfate (ES) and dicarboxylates was assayed for cis-inhibition and/or trans-stimulation in both the uptake and efflux direction. Results: hOAT3-mediated efflux of glutarate (GA), can be significantly trans-stimulated by a variety of ions with high cis-inhibitory potency, including GA (282%), α-ketoglutarate (476%), p-aminohippurate (179%), and, most notably, urate (167%). Urate cis-inhibited ES uptake with an IC₅₀ close to normal serum urate concentrations. Conclusion: These data indicate that OAT3 does not represent a uniporter but operates as an organic ion%dicarboxylate exchanger similar to OAT1, and may mediate renal urate secretion.

Uric acid transport and disease

“…The organic anion and urate transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) can function as urate/ dicarboxylate exchangers (61)(62)(63)(64) and are found on the basolateral side of the same cells that express Oat4 (58). However, Oat3 is also found in all segments of the rat nephron from the proximal tubule to the collecting duct (65).…”

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

“…When expressed in Xenopus oocytes or epithelial cell lines, OAT1 couples OA entry to dicarboxylate exit and was trans-stimulated by preloading with PAH (34). Similarly, OAT3 operates as an organic anion/␣-ketoglutarate exchanger (2), and OAT3-mediated uptake of PAH was transstimulated by glutarate (32). Thus both transporters are candidates for basolateral uptake of OA in the proximal tubule.…”

Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy

“…On the basolateral side of proximal tubular epithelial cells the exit of urate depends on a voltage-dependent transport system, which may be GLUT9 in humans (12) (see below). The basolateral membrane organic anion transporters OAT1 and OAT3 also transport urate (13,14). However, inactivation of either OAT1 or OAT3 slightly decreases uricosuria, suggesting that their principal function may be in urate excretion (10).…”