title: The unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress.
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.
authors.affiliation: INSERM U775, Centre Universitaire des Saints Peres, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bouvier
authors.forename: Sophie
authors.initials: S
authors.lastname: Fougeray
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D013312:Stress, Physiological; D056811:Unfolded Protein Response; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D016222:Fibroblast Growth Factor 2; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D012259:Ribonuclease, Pancreatic; D042461:Vascular Endothelial Growth Factor A; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C497113:Atf6 protein, rat; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; C467484:VEGFA protein, human; C467498:vascular endothelial growth factor A, rat; C403982:ERN2 protein, human; C486557:Ern2 protein, rat; C046366:angiogenin