New insights into epithelial sodium channel function in the kidney: Site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis

Purpose of review: The epithelial sodium channel (ENaC) sets the rate of Na⁺ reabsorption in the collecting duct. This review describes recent advances in our understanding of ENaC function. Recent findings: First, collecting duct-specific deletion of αENaC does not cause Na⁺ wasting in mice, suggesting that other regions can compensate. Second, Nedd4 and Nedd4-2 are ubiquitin ligases that reduce surface expression of ENaC and inhibit Na⁺ transport. Nedd4-2, but not Nedd4, is negatively regulated by serum- and glucocorticoid-inducible kinase 1, an aldosterone-induced kinase, providing an attractive mechanism for the stimulatory effect of aldosterone on Na⁺ transport. However, mice with germline ablation of serum- and glucocorticoid-inducible kinase 1 show only modest hypotension and are able to decrease Na⁺ excretion rates substantially. Third, maturation of ENaC is associated with processing at consensus furin cleavage sites and this cleavage is critical for channel activity. A separate class of serine proteases, the channel-activating proteases, also stimulates ENaC activity. Summary: The connecting tubule of the kidney has abundant ENaC and Na⁺- and K⁺-transport capacity and may provide much of ENaC-mediated Na⁺ transport in the kidney. Aldosterone may increase Na⁺ transport, in part, by serum- and glucocorticoid-inducible kinase 1-mediated inhibition of Nedd4-2 but this has not been demonstrated in the native collecting duct or connecting tubule. The mild phenotype of the serum- and glucocorticoid-inducible kinase 1-knockout mouse points to serum- and glucocorticoid-inducible kinase 1-independent mechanisms that regulate Na⁺ transport. Two separate classes of protease appear to regulate Na⁺ transport: one is furin or furin-like and cleaves ENaC subunits to stimulate transport; the other, the channel-activating proteases, may act on ENaC or a regulatory molecule.