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 microg/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 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, 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 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.
Fejes-Tóth
Geza
G
Dept. of Physiology, Dartmouth School of Medicine, Lebanon, NH, USA.
Frindt
Gustavo
G
Náray-Fejes-Tóth
Aniko
A
Palmer
Lawrence G
LG
D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009318:Natriuresis / Q000502:physiology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D012982:Sodium, Dietary / Q000493:pharmacokinetics*; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D012982:Sodium, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases; C507053:Scnn1g protein, mouse