title: Overexpression of angiotensinogen downregulates aquaporin 1 expression via modulation of Nrf2-HO-1 pathway in renal proximal tubular cells of transgenic mice.
abstract: BACKGROUND
  We aimed to examine the regulation of aquaporin 1 expression in an angiotensinogen transgenic mouse model, focusing on underlying mechanisms.
  
  
  METHODS
  Male transgenic mice overexpressing rat angiotensinogen in their renal proximal tubular cells (RPTCs) and rat immortalised RPTCs stably transfected with rat angiotensinogen cDNA were used.
  
  
  RESULTS
  Angiotensinogen-transgenic mice developed hypertension and nephropathy, changes that were either partially or completely attenuated by treatment with losartan or dual renin-angiotensin system blockade (losartan and perindopril), respectively, while hydralazine prevented hypertension but not nephropathy. Decreased expression of aquaporin 1 and heme oxygenase-1 and increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and sodium-hydrogen exchanger 3 were observed in RPTCs of angiotensinogen-transgenic mice and in angiotensinogen-transfected immortalised RPTCs. These parameters were normalised by dual renin-angiotensin system blockade. Both in vivo and in vitro studies identified a novel mechanism in which angiotensinogen overexpression in RPTCs enhances the cytosolic accumulation of Nrf2 via the phosphorylation of pGSK3β Y216. Consequently, lower intranuclear Nrf2 levels are less efficient to trigger heme oxygenase-1 expression as a defence mechanism, which subsequently diminishes aquaporin 1 expression in RPTCs.
  
  
  CONCLUSIONS
  Angiotensinogen-mediated downregulation of aquaporin 1 and Nrf2 signalling may play an important role in intrarenal renin-angiotensin system-induced hypertension and kidney injury.
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
authors.forename: Shiao-Ying
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
authors.forename: Chao-Sheng
authors.initials: CS
authors.lastname: Lo
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Zhao
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
authors.forename: Min-Chun
authors.initials: MC
authors.lastname: Liao
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Chenier
authors.affiliation: Division of Nephology, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bouley
authors.affiliation: Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada.
authors.forename: John Sd
authors.initials: JS
authors.lastname: Chan
authors.affiliation: Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Canada shao.ling.zhang@umontreal.ca.
authors.forename: Shao-Ling
authors.initials: SL
authors.lastname: Zhang
mesh_terms: D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D051398:Aquaporin 1 / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007150:Immunohistochemistry; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D051176:beta Catenin; D000808:Angiotensinogen; D051398:Aquaporin 1; D051547:Heme Oxygenase-1; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Aquaporin-1; Nrf2; hypertension; intrarenal renin–angiotensin system; kidney injury