Epithelial Na+ channel activation and processing in mice lacking SGK1

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 epithelial Na+ channel (ENaC) protein. Neither SGK1(-/-) mice nor paired SGK1(-/-) animals expressed detectable channel activity, measured as amiloride-sensitive whole-cell current (I-Na), under control conditions with standard chow. Administration of aldosterone (0.5 mu g/h via osmotic minipump for 7 days) increased INa 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 gamma-ENaC, was more pronounced in 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 wild-type mice. Under these conditions, INa was enhanced more in SGK1(-/-) (94 +/- 14 pA/cell) than in SGK(-/-) (23 +/- 5 pA/cell) genotypes. Despite the larger currents, the ratio of cleaved to full-length gamma-ENaC was lower in the knockout animals. The mice also expressed a smaller amount of 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.