Abstract
We examined renal Na and K transporters in mice with deletions in the gene encoding the aldosterone-induced protein SGK1. The knockout mice were hyperkalemic, and had altered expression of the subunits of the epithelial Na channel (ENaC). The kidneys showed decreased expression of the cleaved forms of the γENaC subunit, and the fully glycosylated form of the βENaC subunits when animals were fed a high-K diet. Knockout animals treated with exogenous aldosterone also had reduced subunit processing and diminished surface expression of βENaC and γENaC. Expression of the three upstream Na transporters NHE3, NKCC2, and NCC was reduced in both wild-type and knockout mice in response to K loading. The activity of ENaC measured as whole cell amiloride-sensitive current (INa) in principal cells of the cortical collecting duct (CCD) was minimal under control conditions but was increased by a high-K diet to a similar extent in knockout and wild-type animals. INa in the connecting tubule also increased similarly in the two genotypes in response to exogenous aldosterone administration. The activities of both ROMK channels in principal cells and BK channels in intercalated cells of the CCD were unaffected by the deletion of SGK1. Acute treatment of animals with amiloride produced similar increases in Na excretion and decreases in K excretion in the two genotypes. The absence of changes in ENaC activity suggests compensation for decreased surface expression. Altered K balance in animals lacking SGK1 may reflect defects in ENaC-independent K excretion.
Highlights
THE SERUM and glucocorticoid-induced kinase SGK1 is encoded by a gene whose transcription is among those induced by the mineralocorticoid aldosterone in the mammalian kidney [4, 26, 27]
The first was to examine the SGK1-dependence of the activities of epithelial Na channel (ENaC) as well as other channels and transporters involved in renal K secretion in mice on a diet rich in K, to see if defects in these activities could account for K retention under these conditions
We examined the effects of elimination of SGK1 on the expression of the various forms of the ENaC subunits
Summary
THE SERUM and glucocorticoid-induced kinase SGK1 is encoded by a gene whose transcription is among those induced by the mineralocorticoid aldosterone in the mammalian kidney [4, 26, 27]. Several mouse models lacking expression of SGK1 have been used to test the involvement of the kinase in Na and K homeostasis. Mice with a global knockout of SGK1 had increased plasma aldosterone levels and mild hyperkalemia [37]. The same floxed-Sgk mouse strain was subsequently used to produce a kidney-specific sgk knockout [8]. These animals exhibited Na wasting and hyperaldosteronism on a low-Na diet. The first was to examine the SGK1-dependence of the activities of ENaC as well as other channels and transporters involved in renal K secretion in mice on a diet rich in K, to see if defects in these activities could account for K retention under these conditions. We selected the original SGK1-deficient mouse strain for this work due to the extensive whole animal data available for these animals under conditions of K load [20, 35]
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