SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport

Am J Physiol Renal Physiol. 2001 Feb;280(2):F303-13. doi: 10.1152/ajprenal.2001.280.2.F303.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Immediate-Early Proteins
  • Insulin / pharmacology
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism*
  • Mineralocorticoids / pharmacology
  • Nuclear Proteins*
  • Peptides / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Sodium Channel Blockers
  • Sodium Channels / metabolism*
  • Xenopus laevis

Substances

  • Enzyme Inhibitors
  • Immediate-Early Proteins
  • Insulin
  • Mineralocorticoids
  • Nuclear Proteins
  • Peptides
  • Phosphoinositide-3 Kinase Inhibitors
  • Sodium Channel Blockers
  • Sodium Channels
  • serum sodium transport inhibitor
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase