Epithelial Na+channel activation and processing in mice lacking SGK1

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Abstract
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 ( INa), under control conditions with standard chow. Administration of aldosterone (0.5 μg/h via osmotic minipump for 7 days) increased INato 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 γ-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, INawas 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 γ-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.

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