title: Effect of angiotensin II and small GTPase Ras signaling pathway inhibition on early renal changes in a murine model of obstructive nephropathy.
abstract: Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain ; Centro de Investigación del Cáncer (CSIC), Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Rodríguez-Peña
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fuentes-Calvo
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain ; Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Docherty
authors.affiliation: Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain ; Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arévalo
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain ; Universidad Francisco de Vitoria, 28223 Madrid, Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Grande
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain ; Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Nélida
authors.initials: N
authors.lastname: Eleno
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain ; Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pérez-Barriocanal
authors.affiliation: Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de Investigación Nefrológica, Fundación Renal Iñigo Alvarez de Toledo, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain ; Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: López-Novoa
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014517:Ureteral Obstruction / Q000178:diet therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000069059:Atorvastatin; D020559:Monomeric GTP-Binding Proteins
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