SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport

Jian Wang, Pascal Barbry, Anita C. Maiyar, David J. Rozansky, Aditi Bhargava, Meredith Leong, Gary L. Firestone, David Pearce

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

The epithelial Na+ channel (ENaC) constitutes the rate-limiting step for Na+ transport across tight epithelia and is the principal target of hormonal regulation, particularly by insulin and mineralocorticoids. Recently, the serine-threonine kinase (SGK) was identified as a rapidly mineralocorticoid-responsive gene, the product of which stimulates ENaC-mediated Na+ transport. Like its close relative, protein kinase B (also called Akt), SGK's kinase activity is dependent on phosphatidylinositol 3-kinase (PI3K), a key mediator of insulin signaling. In our study we show that PI3K is required for SGK-dependent stimulation of ENaC-mediated Na+ transport as well as for the production of the phosphorylated form of SGK. In A6 kidney cells, mineralocorticoid induction of the phosphorylated form of SGK preceded the increase in Na+ transport, and specific inhibition of PI3K inhibited both phosphorylation of SGK and mineralocorticoid-induced Na+ transport. Insulin both augmented SGK phosphorylation and synergized with mineralocorticoids in stimulating Na+ transport. In a Xenopus laevis oocyte coexpression assay, SGK-stimulated ENaC activity was also markedly reduced by PI3K inhibition. Finally, in vitro-translated SGK specifically interacted with the ENaC subunits expressed in Escherichia coli as glutathione S-transferase fusion proteins. These data suggest that SGK is a PI3K-dependent integrator of insulin and mineralocorticoid actions that interacts with ENaC subunits to control Na+ entry into kidney collecting duct cells.

Original languageEnglish (US)
Pages (from-to)F303-F313
JournalAmerican Journal of Physiology - Renal Physiology
Volume280
Issue number2 49-2
DOIs
StatePublished - Feb 2001

Keywords

  • Epithelial sodium channel
  • Phosphatidylinositol 3-kinase
  • Serine-threonine kinase

ASJC Scopus subject areas

  • Physiology
  • Urology

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