New insights into the role of serum- and glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure

Curr Opin Nephrol Hypertens. 2005 Jan;14(1):59-66. doi: 10.1097/00041552-200501000-00010.

Abstract

Purpose of review: The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. We describe recent advances in our understanding of SGK1 function in the regulation of renal function and blood pressure.

Recent findings: Thiazolidinediones, i.e. activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), upregulate SGK1 and ENaC mRNA expression and increase cell-surface expression of ENaC alpha in a human cortical-collecting-duct cell line. cAMP/protein kinase A can induce phosphorylation and inhibition of Nedd4-2-independent of SGK1. Part of ENaC stimulation by SGK1 appears dependent on a SGK1 consensus motif in ENaC alpha and independent of Nedd4-2. SGK1-dependent upregulation of Na+ reabsorption in ASDN contributes to upregulation of renal K+ excretion. In oocytes, SGK1 activates various renal transport proteins including Na+/glucose cotransporter SGLT1, Na+-coupled dicarboxylate transporter NaDC-1, epithelial Ca+ channel TRPV5, renal outer medullary K+ channel ROMK and voltage gated K+ channels KCNE1/KCNQ1 and Kv1.3. A variant of the SGK1 gene associates with increased blood pressure and body mass index.

Summary: PPAR gamma activators may increase renal Na reabsorption by stimulating SGK1 and ENaC. Nedd4-2 integrates influences of cAMP/protein kinase A and SGK1. SGK1 can activate ENaC in part directly and independent of Nedd4-2. K+ homeostasis requires SGK1-dependent Na+ reabsorption in ASDN. SGK1 may affect renal transport mechanisms beyond Na+ reabsorption and K+ secretion in ASDN. Polymorphisms of SGK1 may be relevant to the pathophysiology of hypertension and other diseases.

Publication types

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

MeSH terms

  • Blood Pressure / physiology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Humans
  • Immediate-Early Proteins
  • Kidney Tubules, Distal / metabolism
  • Kidney Tubules, Distal / physiology*
  • Nuclear Proteins / metabolism*
  • PPAR gamma / metabolism
  • Polymorphism, Genetic
  • Potassium / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sodium / metabolism
  • Sodium Channels / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Up-Regulation

Substances

  • Immediate-Early Proteins
  • Nuclear Proteins
  • PPAR gamma
  • Sodium Channels
  • Sodium
  • WWP2 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Cyclic AMP-Dependent Protein Kinases
  • Potassium