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EDITORIAL FOCUS

Epithelial Na⁺ channel activation and processing in mice lacking SGK1

¹Department of Physiology, Dartmouth School of Medicine, Lebanon, Hew Hampshire; and ²Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York

Submitted 4 December 2007 ; accepted in final form 26 March 2008

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 µg/h 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 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, I_Na 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 -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.

epithelial sodium channel; proteolysis; sodium reabsorption; cortical collecting duct

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