title: Endothelin-1 Drives Epithelial-Mesenchymal Transition in Hypertensive Nephroangiosclerosis.
abstract: Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin-1 (ET-1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET-1.
  
  
  
  Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II-dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET-1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of E-cadherin and α-smooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HK-2 proximal tubular cells expressing the ETB receptor subtype, the effects of ET-1 with or without ET-1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased E-cadherin and increased αSMA expression. Irbesartan and the mixed ET-1 receptor antagonist bosentan prevented these changes in a blood pressure-independent fashion (P < 0.001 for both versus controls). In HK-2 cells ET-1 blunted E-cadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ETB receptor antagonist BQ-788. Evidence for involvement of the Rho-kinase signaling pathway and dephosphorylation of Yes-associated protein in EMT was also found.
  
  
  
  In angiotensin II-dependent hypertension, ET-1 acting via ETB receptors and the Rho-kinase and Yes-associated protein induces EMT and thereby renal fibrosis.
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Seccia
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Brasilina
authors.initials: B
authors.lastname: Caroccia
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gioco
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Piazza
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Buccella
authors.affiliation: Human Anatomy, Department of Molecular Medicine, University of Padua, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Guidolin
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Guerzoni
authors.affiliation: Immunology, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Montini
authors.affiliation: Human Anatomy, Department of Molecular Medicine, University of Padua, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Petrelli
authors.affiliation: Nephrology Divisions, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.affiliation: Nephrology Divisions, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Verdiana
authors.initials: V
authors.lastname: Ravarotto
authors.affiliation: Human Anatomy, Department of Molecular Medicine, University of Padua, Italy.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Belloni
authors.affiliation: Nephrology Divisions, Department of Medicine-DIMED, University of Padua, Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Calò
authors.affiliation: Internal Medicine, Department of Medicine-DIMED, University of Padua, Italy gianpaolo.rossi@unipd.it.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Rossi
mesh_terms: D000199:Actins / Q000187:drug effects* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001713:Biphenyl Compounds / Q000494:pharmacology; D000077300:Bosentan; D015820:Cadherins / Q000187:drug effects* / Q000378:metabolism; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005355:Fibrosis; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000378:metabolism*; D000077405:Irbesartan; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D000077300:Bosentan; D015820:Cadherins; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D000077405:Irbesartan; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D013777:Tetrazoles; D054460:rho-Associated Kinases; C541116:ACTA2 protein, human; C498862:Acta2 protein, rat; C086539:BQ 788
keywords: endothelin‐1; epithelial to mesenchymal transition; fibrosis; hypertension; kidney