Feedback inhibition of ENaC during acute sodium loading in vivo

Abstract

The epithelial Na+channel (ENaC) is tightly regulated by sodium intake to maintain whole body sodium homeostasis. In addition, ENaC is inhibited by high levels of intracellular Na+[Na+]i, presumably to prevent cell Na+overload and swelling. However, it is not clear if this regulation is relevant in vivo. We show here that in rats, an acute (4 h) oral sodium load decreases whole-cell amiloride-sensitive currents ( INa) in the cortical collecting duct (CCD) even when plasma aldosterone levels are maintained high by infusing the hormone. This was accompanied by decreases in whole-kidney cleaved α-ENaC (2.6 fold), total β-ENaC (1.7 fold), and cleaved γ-ENaC (6.2 fold). In addition, cell-surface β- and γ-ENaC expression was measured using in situ biotinylation. There was a decrease in cell-surface core-glycosylated (2.2 fold) and maturely glycosylated (4.9 fold) β-ENaC and cleaved γ-ENaC (4.7 fold). There were no significant changes for other apical sodium transporters. To investigate the role of increases in Na+entry and presumably [Na+]ion ENaC, animals were infused with amiloride prior to and during sodium loading. Blocking Na+entry did not inhibit the effect of resalting on INa. However, amiloride did prevent decreases in ENaC expression, an effect that was not mimicked by hydrochlorothiazide administration. Na+entry and presumably [Na+]ican regulate ENaC expression but does not fully account for the aldosterone-independent decrease in INaduring an acute sodium load.