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.