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BioMed Research International
Volume 2014, Article ID 124902, 14 pages
http://dx.doi.org/10.1155/2014/124902
Research Article

Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

1Unidad 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
2Centro de Investigación del Cáncer (CSIC), Universidad de Salamanca, 37007 Salamanca, Spain
3Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
4Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain
5Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, 37007 Salamanca, Spain
6Universidad Francisco de Vitoria, 28223 Madrid, Spain

Received 27 February 2014; Revised 12 May 2014; Accepted 6 June 2014; Published 3 July 2014

Academic Editor: Akito Maeshima

Copyright © 2014 Ana B. Rodríguez-Peña et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.