Feedback inhibition of ENaC during acute sodium loading in vivo

Patel AB, Frindt G, Palmer LG. Feedback inhibition of ENaC during acute sodium loading in vivo. Am J Physiol Renal Physiol 304: F222-F232, 2013. First published November 21, 2012; doi:10.1152/ajprenal.00596.2012.-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 (I-Na) 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 alpha-ENaC (2.6 fold), total beta-ENaC (1.7 fold), and cleaved gamma-ENaC (6.2 fold). In addition, cell-surface beta- and gamma-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) beta-ENaC and cleaved gamma-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+](i) on ENaC, animals were infused with amiloride prior to and during sodium loading. Blocking Na+ entry did not inhibit the effect of resalting on I-Na. However, amiloride did prevent decreases in ENaC expression, an effect that was not mimicked by hydrochlorothiazide administration. Na+ entry and presumably [Na+](i) can regulate ENaC expression but does not fully account for the aldosterone-independent decrease in I-Na during an acute sodium load.