Serum- and glucocorticoid-regulated kinase 1 is upregulated following unilateral ureteral obstruction causing epithelial-mesenchymal transition

Kidney Int. 2010 Oct;78(7):668-78. doi: 10.1038/ki.2010.214. Epub 2010 Jul 14.

Abstract

Obstructive nephropathy leads to chronic kidney disease, characterized by a progressive epithelial-to-mesenchymal cell transition (EMT)-driven interstitial fibrosis. To identify the mechanisms causing EMT, we used the mouse model of unilateral ureteral obstruction and found a rapid and significant increase in serum- and glucocorticoid-regulated kinase-1 (SGK1) expression in the kidneys with an obstructed ureter. Knockout of SGK1 significantly suppressed obstruction-induced EMT, kidney fibrosis, increased glycogen synthase kinase-3β activity, and decreased accumulation of the transcriptional repressor Snail. This caused a reduced expression of the mesenchymal marker α-smooth muscle actin, and collagen deposition in this model. In cultured kidney epithelial cells, mechanical stretch or treatment with transforming growth factor-β not only stimulated the transcription of SGK1, but also stimulated EMT in an SGK1-dependent manner. Activated SGK1 stimulated Snail accumulation and downregulation of the epithelial marker E-cadherin. Hence, our study shows that SGK1 is involved in mediating fibrosis associated with obstructive nephropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cells, Cultured
  • Epithelial-Mesenchymal Transition*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Immediate-Early Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / physiology*
  • Snail Family Transcription Factors
  • Stress, Mechanical
  • Transcription Factors / physiology
  • Transforming Growth Factor beta / pharmacology
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology

Substances

  • Cadherins
  • Immediate-Early Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Glycogen Synthase Kinase 3