Renal proximal tubule secretion of urate is regulated by a stress‐induced pathway

Abstract

Urate is an important antioxidant at normal plasma concentrations (~ 300 µM) in both birds and humans, and is the major nitrogenous waste in birds. Plasma urate concentrations are primarily regulated by urinary excretion, and ~70% of renal urate excretion is due to tubular secretion. The steps in tubular secretion include basolateral entry via Oat1/3‐like transport and apical membrane exit through Mrp4 transport. Factors that regulate this pathway remain uncertain. Cellular stress has been shown to affect transport properties in other systems by altering both stress protein levels and transporter expression or activity. Here, the effect of zinc‐induced cell stress on active transepithelial urate secretion by chicken renal proximal tubule epithelial cell monolayers was determined. Direct measure of net secretion following a six‐hour conditioning stress with 250 µM ZnCl2, then 1.5 hour zinc‐free recovery, inhibited urate transport with no change in Mrp4 expression, as shown by fluorescence immunohistochemistry and real‐time PCR, and no change in glucose transport or transepithelial resistance. Acute exposure to zinc had no effect suggesting involvement of a cellular adaptation to stress. Preliminary data show an AMP kinase activator (AICAR, 0.1 mM) strongly inhibited urate secretion. We tentatively conclude that cellular stress may inhibit active renal urate secretion. Supported by NSF.