Avaliação dos distúrbios metabólicos produzidos pela deleção genética do receptor de angiotensina - (1-7), mas, em camundongos FVB/N

Abstract

The metabolic syndrome, also known as insulin resistance syndrome, is characterized by the variable coexistence of obesity, insulin resistance, dislipidemy and hypertension. The angiotensin-(1-7) presents an important contaregulatory role inside Renin Angiotensin System, opposing some times to angiotensina II effects. It has been shown that G protein-coupled receptor, Mas, mediates many actions of angiotensin-(1-7). We have recently observed that Mas-knockout male mice (Mas-/-) in the pure, FVB/N genetic background, presents elevated blood pressure levels and endothelial dysfunction, alterations present in the metabolic syndrome. The aim of this study was to ascertain whether genetic deletion of Mas also changes lipidic and glycemic profile and the mechanisms of these alterations. Ten weeks old Mas-/- and WT mice were used. Curves of plasma glycemia versus time were built after intraperitoneal application of insulin (0.75U/Kg BW) or glucose (2g/Kg BW). After sacrifice, the tissues were weighted and reserved for western blotting and Real-Time PCR. The lipidic profile and the plasma levels of leptin and adiponectin were analyzed using ELISA kits and TGF-â, angiotensinogen and TNF-á mRNA expression was analyzed by Real Time PCR. Despite of having normal body weight (24.7 ± 0.35 vs 24.8± 0.24 g in WT), young Mas-/- mice presented a marked increase in the fat tissue mass (epididimal= 1.704 ± 0.1516 vs 1.150 ± 0.1259 % of BW in WT and retroperitoneal= 0.6747 ± 0.08576 vs 0.3781 ± 0.04575 % of BW in WT). In addition, these animals presented a state of insulin resistance and glucose intolerance as well as an increase in the fasting glycemia levels (86.6 ± 6.43 vs 56.40 ± 4.98 mg/dl in WT). Furthermore, a significant increase in total cholesterol (92.2 ± 3.65 vs 74.6± 5.67 mg/dl in WT) and triglycerides (70.6 ± 13.3 vs 41.4± 4.07 mg/dl in WT) levels were observed. Part of these alterations can be explained by the increase in the leptin plasma levels (1.3 ± 0.25 vs 0.73 ± 0.17 ng/ml in WT) and the decreased Glut4 receptor protein in Mas-/- adipose tissue. The mRNA expression of TGF-â and angiotensinogen was increased in Mas-/- adipose tissue, while the expression of TNF-á, the food intake and adiponectin plasma levels, were not altered. These results show that Mas deficiency in FVB/N mice leads to dramatic changes in glicemic and lipidic metabolism, inducing a metabolic syndrome- like state.