Contrasting effects of aliskiren versus losartan on hypertensive vascular remodeling

Background: Hyperactivation of the renin-angiotensin system contributes to hypertension-induced upregulation of vascular matrix metalloproteinases (MMPs) and remodeling, especially in the two kidney, one clip (2K1C) hypertension model. We hypothesized that the AT(1)R antagonist losartan or the renin inhibitor aliskiren, given at doses allowing similar antihypertensive effects, could prevent in vivo vascular MMPs upregulation and remodeling, and collagen/elastin deposition found in 2K1C hypertension by preventing the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and transforming growth factor-beta(1) (TGF-beta(1)). We also hypothesized that aliskiren could enhance the effects of losartan.Methods: 2K1C rats were treated with aliskiren (50 mg.kg(-1).day(-1)), or losartan (10 mg.kg(-1).day(-1)), or both by gavage during 4 weeks.Results: Aliskiren, losartan, or both drugs exerted similar antihypertensive effects when compared with 2K1C rats treated with water. Aliskiren reduced plasma renin activity in both sham and 2K-1C rats. Losartan alone or combined with aliskiren, but not aliskiren alone, abolished 2K1C-induced aortic hypertrophy and hyperplasia, and prevented the increases in aortic collagen/elastin content, MMP-2 levels, gelatinolytic activity, and expression of phospho-ERK 1/2 and TGF-beta(1). No significant differences were found in the aortic expression of the (pro) renin receptor.Conclusions: These findings show that although losartan and aliskiren exerted similar antihypertensive effects, only losartan prevented the activation of vascular profibrotic mechanisms and MMP upregulation associated with vascular remodeling in 2K1C hypertension. Our findings also suggest that aliskiren does not enhance the protective effects exerted by losartan. (C) 2012 Elsevier Ireland Ltd. All rights reserved.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univ São Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP, BrazilUniv São Paulo, Fac Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilUniv São Paulo, Dent Sch Ribeirao Preto, Dept Morphol Estomatol & Physiol, BR-14049900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Dept Med, Div Nephrol, São Paulo, BrazilWeb of Scienc