Exposure to GH induces a downregulation of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in heart and kidney.

MUÑOZ MC; BURGHI V; MAZZIOTTA L; BANEGAS D; DOMINICI FP

Minas Gerais

Simposio; IX International Symposium on Vasoactive Peptides; 2013

Cardiovascular and renal diseases are commonly associated with alterations of the GH/IGF-1 axis and involve an imbalance within the renin-angiotensin system (RAS). However, there is scant information available regarding the effects of disturbances in the GH/IGF-1 axis on the in vivo expression of the main components of the renin-angiotensin-system (RAS).The two major peptides of the RAS, angiotensin (Ang) II and Ang-(1?7) have opposing cardiovascular effects. Ang II is generated through hydrolysis of Ang I by ACE. Ang II has been shown to interact with AT1 and AT2 receptors. AT1 receptor activation promotes vasoconstriction, reactive oxygen species production, stimulates extracellular matrix remodeling and inflammation response which leads to tissue injury. On the other hand, activation of the AT2 receptor (AT2R) is associated with inhibition of cell growth, inflammation and fibrosis; and exerts a cardio-protective role against ischemia-reperfusion injury and acute myocardial infarction. The axis formed by ACE2/Ang-(1?7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, opposing  the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT1R. In the current work, we tested the hypothesis that overexpression of GH in mice leads to a shift in the expression of cardiac and renal main components of the RAS towards a negative status of this system that could explain at least in part their hypertension, cardiovascular and renal damage. We evaluated local levels of Ang II and Ang-(1-7); AT1R, AT2R and Mas, as well as ACE, ACE2 in the heart and the kidney of transgenic mice overexpressing bovine GH (PEPCK-bGH mice) by both immunohistochemistry and Western blotting analysis. We observed decreased levels of Masreceptor and ACE2 in both tissues. Unexpectedly AT1R was reduced in heart and kidney of PEPCK-bGH mice. AT2R was decreased in the kidney and unaltered in the heart. ACE levels remained unaltered in the heart and the kidney of transgenic mice. The shift within the RAS towards an attenuation of the ACE2/Ang-(1-7)/Mas receptor axis observed in PEPCK-bGH mice may contribute to the increased incidence of hypertension and cardiovascular disfunction displayed by this animal model of acromegaly.