Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule

Abstract

Uric acid (urate) is the end product of purine metabolism in humans. Human kidneys reabsorb a large proportion of filtered urate. This extensive renal reabsorption, together with the fact that humans do not possess uricase that catalyzes the biotransformation of urate into allantoin, results in a higher plasma urate concentration in humans compared to other mammals. A major determinant of plasma urate concentration is renal excretion as a function of the balance between reabsorption and secretion. We previously identified that renal urate absorption in proximal tubular epithelial cells occurs mainly via apical urate/anion exchanger, URAT1/SLC22A12, and by facilitated diffusion along the trans-membrane potential gradient by the basolateral voltage-driven urate efflux transporter, URATv1/SLC2A9/GLUT9. In contrast, the molecular mechanism by which renal urate secretion occurs remains elusive. Recently, we reported a newly characterized human voltage-driven drug efflux transporter, hNPT4/SLC17A3, which functions as a urate exit pathway located at the apical side of renal proximal tubules. This transporter protein has been hypothesized to play an important role with regard to net urate efflux. An in vivo role of hNPT4 is supported by the fact that missense mutations in SLC17A3 present in hyperuricemia patients with urate underexcretion abolished urate efflux capacity in vitro. Herein, we report data demonstrating that loop diuretics and thiazide diuretics substantially interact with hNPT4. These data provide molecular evidence for loop and thiazide-diuretics-induced hyperuricemia. Thus, we propose that hNPT4 is an important transepithelial proximal tubular transporter that transports diuretic drugs and operates functionally with basolateral organic anion transporters 1/3 (OAT1/OAT3).

Individualising the dose of allopurinol in patients with gout

“…As was the case with reduced renal function, we found that concomitant use of diuretics did not significantly alter the concentration –response to oxypurinol or dose –response relationship to allopurinol. Diuretics decrease not only the renal transport of urate ( via inhibition of proximal tubule transporters ) but also the clearance of oxypurinol . Similar to the effect of renal impairment on urate and oxypurinol clearance, the reductions in oxypurinol clearance results in higher plasma concentrations, which negates the decrease in urate clearance.…”

Predictors of Hyperuricemia after Kidney Transplantation: Association with Graft Function

“…In the general population, diuretics are one of the most important causes of secondary HU. Loop diuretics and thiazide diuretics interact with renal organic anion transporters (OAT), entering the proximal tubular cell from the blood side via OAT1 and OAT3 transporters may be considered as competitive substrates of uric acid [30]. Moreover, diuretics reduce uric acid excretion, presumably by causing mild volume depletion with enhancement of proximal tubular reabsorption [31].…”

Pharmacological Properties of Loop Diuretics and Their Clinical Effects

“…КЛИНИЧЕСКИЕ СЕМИНАРЫ § канальца, снижает секрецию ОАи диуретиков. Уремия и метаболический ацидоз -типические состояния, ведущие к резистентности к диуретикам [15,28]. Лечение ХБП состоит не только в контроле отеков, но и АГ, метаболического ацидоза и гиперкалиемии.…”