Amiloride-sensitive Na⁺-channel activity was examined in the cortical collecting ducts of a mouse line (SGK1^-/-) deficient in the serum- and glucocorticoid-dependent protein kinase SGK1. This activity was correlated with changes in renal Na handling and in the maturation of Na⁺ channel (ENaC) protein. Neither SGK1^-/- mice nor paired SGK1^+/+ animals expressed detectable channel activity, measured as amiloride-sensitive whole-current (I_Na), under control conditions with standard chow. Administration of aldosterone (0.5 µg/hour via osmotic minipump for 7 days) increased I_Na to a similar extent in SGK1^+/+ (378 ± 61 pA/cell at -100 mV) and in SGK1^-/- (350 ± 57 pA/cell) animals. However, the maturation of ENaC, assessed as the ratio of cleaved to full-length forms of ENaC, was more pronounced in the SGK^+/+ mice. The SGK1^-/- animals exhibited a salt-wasting phenotype when kept on a low-Na diet for up to 2 days, losing significantly more Na in the urine than did the wild-type mice. Under these conditions, I_Na was enhanced in the SGK1^-/- (94 ±14 pA/cell) compared with SGK^+/+ (23± 5 pA/cell). Despite the larger currents, the ratio of cleaved/full length ENaC was lower in the knock-out animals. The mice also expressed a smaller amount of the Na-Cl cotransporter protein under Na-depleted conditions. These results indicated that SGK1 is essential for optimal processing of ENaC but is not required for activation of the channel by aldosterone.