The Serum and Glucocorticoid Kinase sgk Increases the Abundance of Epithelial Sodium Channels in the Plasma Membrane of Xenopus Oocytes

Abstract

The serum-and glucocorticoid-induced kinase (sgk) is a serine and threonine kinase that stimulates amiloridesensitive sodium transport in Xenopus oocytes. Because aldosterone induces phosphorylation on serine/threonine (Ser/Thr) residues in the carboxyl termini of ␤ and ␥ subunits of epithelial sodium channels (ENaCs) and causes an increase in the sgk transcript in mammalian and amphibian renal epithelial cells, it seems likely that sgk mediates the action of aldosterone to stimulate sodium transport. Experiments were performed in Xenopus oocytes to determine the mechanism by which sgk increases sodium conductance by examining its effect on phosphorylation, kinetics, and membrane abundance of ENaC. Our results demonstrate that deletions of the carboxyl termini of the three subunits do not inhibit sgk-induced sodium current, indicating that the effect of sgk is not mediated via phosphorylation within the carboxyl termini of ENaC. They also show no evidence that sgk reduces the removal of ENaC from the plasma membrane because mutations of tyrosine residues in the sequences necessary for endocytosis and degradation did not affect the response to sgk. Further studies performed with the patch-clamp technique indicated that sgk did not increase the open probability or changed the kinetics of ENaC. These studies, however, showed a 3-fold increase in the abundance of ENaC in the plasma membrane in the presence of sgk compared with control. Together, the experiments indicate that sgk stimulates electrogenic sodium transport by increasing the number of ENaCs at the cell surface and suggest that sgk may mediate the early increase in aldosterone-induced sodium current.

Lack of the serum and glucocorticoid-inducible kinase SGK1 attenuates the volume retention after treatment with the PPARγ agonist pioglitazone

“…The actions of the PPARγ agonist pioglitazone on the distal nephron strongly resemble the actions of aldosterone, which also exerts both, SGK1-independent direct [3] and SGK1-dependent indirect effects on ENaC expression and activity [1,10,13,29,34]. As part of a counter-regulation to the pioglitazone-induced volume retention, endogenous aldosterone levels were suppressed.…”

“…Treatment with triamterene prevented the body weight gain in sgk1 +/+ mice, an observation indeed pointing to the involvement of ENaC in pioglitazone-induced volume retention. ENaC is regulated by SGK1, which stimulates ENaC expression and activity [1,10,13,29,34]. Interestingly, sgk1 −/− mice under combined treatment were more susceptible to the diuretic action of triamterene and continued to lose weight over the treatment period.…”

“…SGK1 is expressed in the aldosterone-sensitive distal nephron [31], where it stimulates the epithelial Na + channel ENaC [1,10,13,29,34]. Beyond that, SGK1 has been shown to stimulate a wide variety of further renal and extrarenal ion channels and transporters [28].…”

A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's α-Subunit

“…This has been reported to result in an inhibition of Nedd4-2-mediated ubiquitination, endocytic retrieval, and proteasomal degradation of ENaC, thereby increasing the number of functional ENaC channels in the plasma membrane (27,28). However, there is disagreement as to whether the stimulatory effect of SGK1 on ENaC surface expression is primarily mediated by a decrease in removal from or an increase in translocation to the plasma membrane (23,29). Finally, in addition to its stimulatory effect on ENaC surface expression, SGK1 may also increase ENaC open probability (30).…”

SGK1 regulation by miR-466g in cortical collecting duct cells

“…In particular, aldosterone stimulates expression of SGK1 in the late distal convoluted tubule, connecting segment, and collecting duct (7,8,18,25,27), which together constitute the aldosterone-sensitive distal nephron. In turn, SGK1 stimulates ENaC activity through several mechanisms, including an increase in the number and residency time of ENaC in the apical membrane (3,10,21,25,32) and an increase in open probability of ENaC (2,11,34,37). SGK1 knockout mouse models have largely recapitulated the findings of cell culture models of SGK1 action; there are now three SGK1 knockout mouse models from independent groups demonstrating alterations in urinary Na ϩ excretion and blood pressure regulation (14,15,39).…”