Upregulation of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in heart and kidney of growth hormone receptor knockout mice.

GIANI JF; MIQUET JG; MUÑOZ MC; BURGHI V; TOBLLI JE; BARTKE A; TURYN D ; DOMINICI FP

Congreso; Interamerican Socieyt of Hypertension; 2011

American Heart Association

Deletion of growth hormone (GH) receptor (GHR) gene leads to GH resistance, reduced body size, enhanced insulin sensitivity and increased lifespan. Additionally, GHR knock-out mice (GHR-/-) display decreased systolic blood pressure, reduced plasma renin and increased aortic endothelial nitric oxide synthase expression. Although pharmacological antagonism of the classical angiotensin-converting enzyme (ACE)/Angiotensin (Ang) II/AT1 receptor axis resembles the GHR-/- phenotype, there is no information available regarding how disturbances in GH levels may affect the expression of the main components of the renin-angiotensin system (RAS). Therefore, in this study we evaluated the relationship between GH resistance and the abundance of different RAS components in heart and kidney of GHR-/- mice. Thus, local levels of Ang II and Ang-(1-7), AT1, AT2 and Mas receptor, as well as ACE and ACE2 protein abundance were evaluated by immunohistochemistry (IHQ) and western blotting (WB) in heart and kidney. As observed by IHQ, no differences in Ang II content were detected between normal and GHR-/- mice in any tissue analyzed. However, an increase in Ang-(1-7) abundance was observed both in heart (6.4 fold, p<0.002) and kidney (1.7 fold; p<0.002) from GHR-/-. In addition, GHR-/- mice displayed a reduction in the expression of AT1 receptor in heart and kidney (80% for both tissues, p<0.002) together with an increased expression of Mas receptor (1.8 fold for both tissues, p<0.002) compared to their littermates. The expression of AT2 receptor was increased (1.2 fold, p<0.06) in the heart of GHR-/- mice, while renal AT2 receptor abundance remained unaltered. The levels of ACE were similar in both tissues. However, the analysis of ACE2 revealed that GHR-/- mice showed an increased expression of this enzyme (1.5 fold in heart and 2.8 fold in kidney, p<0.002 in both cases). All results were confirmed by WB analyses. The imbalance within the renin-angiotensin system towards the exacerbation of the ACE2/Ang-(1-7)/Mas receptor axis observed both in heart and kidney of GHR-/- mice could play a protective role in cardiac and renal profiles; possibly, contributing to delayed aging and increased lifespan of this animal model.