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

Orlando

Congreso; High Blood Pressure Research 2011 Scientific Sessions, American Heart Association; 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, protection against diabetic nephropathy 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 of GHR-/- mice. 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 misbalance within the reninangiotensin 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.