The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress

J Biol Chem. 2012 Apr 27;287(18):14557-68. doi: 10.1074/jbc.M112.340570. Epub 2012 Mar 8.

Abstract

Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1α pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and angiogenin (ANG) in human kidney epithelial cells independently of HIF-1α. Glucose deprivation, but not hypoxia, triggered endoplasmic reticulum stress and activated the UPR. RNA interference-mediated inhibition of the gene encoding the kinase PERK decreased VEGFA and bFGF expression, but neither gene was affected by the inhibition of IRE1α or ATF6. Furthermore, we show that the expression of angiogenin, which inhibits protein synthesis, is regulated by both IRE1α and PERK, which could constitute a complementary function of the UPR in the repression of translation. In a rat model of acute ischemic stress, we show that the UPR is activated in parallel with VEGFA, bFGF, and ANG expression and independently of HIF-1α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism
  • Animals
  • Cell Line
  • Endoribonucleases / metabolism
  • Epithelium / metabolism
  • Epithelium / pathology
  • Fibroblast Growth Factor 2 / metabolism
  • Gene Expression Regulation
  • Glucose / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Kidney / blood supply*
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Membrane Proteins / metabolism
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ribonuclease, Pancreatic / metabolism
  • Stress, Physiological*
  • Unfolded Protein Response*
  • Vascular Endothelial Growth Factor A / metabolism
  • eIF-2 Kinase / metabolism

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Atf6 protein, rat
  • HIF1A protein, human
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Membrane Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Fibroblast Growth Factor 2
  • ERN2 protein, human
  • Ern2 protein, rat
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • Endoribonucleases
  • angiogenin
  • Ribonuclease, Pancreatic
  • Glucose