title: Role of the transcription factor erythroblastosis virus E26 oncogen homolog-1 (ETS-1) as mediator of the renal proinflammatory and profibrotic effects of angiotensin II.
abstract: Angiotensin II (Ang II) plays a major role in the pathogenesis of end-organ injury in hypertension via its diverse hemodynamic and nonhemodynamic effects. Erythroblastosis virus E26 oncogen homolog-1 (ETS-1) is an important transcription factor recently recognized as an important mediator of cell proliferation, inflammation, and fibrosis. In the present studies, we tested the hypothesis that ETS-1 is a common mediator of the renal proinflammatory and profibrotic effects of Ang II. C57BL6 mice (n=6 per group) were infused with vehicle (control), Ang II (1.4 mg/kg per day), Ang II and an ETS-1 dominant-negative peptide (10 mg/kg per day), or Ang II and an ETS-1 mutant peptide (10 mg/kg per day) via osmotic minipump for 2 or 4 weeks. The infusion of Ang II resulted in significant increases in blood pressure and left ventricular hypertrophy, which were not modified by ETS-1 blockade. The administration of ETS-1 dominant-negative peptide significantly attenuated Ang II-induced renal injury as assessed by urinary protein excretion, mesangial matrix expansion, and cell proliferation. Furthermore, ETS-1 dominant-negative peptide but not ETS-1 mutant peptide significantly reduced Ang II-mediated upregulation of transforming growth factor-β, connective tissue growth factor, and α-smooth muscle actin. In addition, ETS-1 blockade reduced several proinflammatory effects of Ang II, including macrophage infiltration, nitrotyrosine expression, and NOX4 mRNA expression. Our studies suggest that ETS-1 is a common mediator of the proinflammatory and profibrotic effects of Ang II-induced hypertensive renal damage and may result in the development of novel strategies in the treatment and prevention of end-organ injury in hypertension.
authors.affiliation: Division of Nephrology, University of Alabama at Birmingham, Ziegler Research Building 637, 1530 3rd Ave South, Birmingham, AL 35294, USA.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Feng
authors.forename: Phillip
authors.initials: P
authors.lastname: Chumley
authors.forename: Ping
authors.initials: P
authors.lastname: Hua
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rezonzew
authors.forename: David
authors.initials: D
authors.lastname: Jaimes
authors.forename: Madison W
authors.initials: MW
authors.lastname: Duckworth
authors.forename: Dongqi
authors.initials: D
authors.lastname: Xing
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D005355:Fibrosis / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007249:Inflammation / Q000517:prevention & control; D019394:Ki-67 Antigen / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C494042:Ets1 protein, mouse; D019394:Ki-67 Antigen; D010455:Peptides; D050784:Proto-Oncogene Protein c-ets-1; D000804:Angiotensin II; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse