0194 : Angiotensin II type 2 receptor reduces metabolic and vascular effects of type 1 diabetes in the mouse

The renin-angiotensin system has a key role in cardiovascular homeostasis, mainly through activation of angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors. Although AT2R opposes the effects of AT1R, with vasodilator and antitrophic properties, its effect in diabetes remains debated. Thus we determined the role of AT2R in endothelium-mediated dilation in a mouse model of type 1 diabetes. Diabetes was induced in three-month-old mice by streptozotocin (150mg/kg, ip). After 45 days, mesenteric resistance arteries were isolated and mounted on a wire myograph to measure vascular reactivity. The absence of AT2R reduced glucose tolerance and body weight and increased STZ-induced hyperglycemia, hyperinsulinemia, creatiniemia, blood thromboxaneA2, PGF2alpha and isoprostane. AT2R, COX-2 and NADPHoxidase subunits (gp91phox and p22phox) gene expression were higher in arteries of diabetic mice than in control animals. COX-2 level and oxidative stress were also higher in mesenteric and renal arteries in AT2R-/- mice. Endothelium-dependent relaxation, reduced in diabetic mice arteries, was normalized after cycloxygenase-2 (COX-2) (CAY10404) blockade or ROS reduction with tempol plus catalase in both AT2R-/- and AT2R+/+ mice. AT2R-dependent dilation in isolated perfused mesenteric arteries was greater in diabetic mice than in control animals. Thus, in a model of type 1 diabetes AT2R reduces the severity of diabetes possibly through a reduction of the production of ROS and COX-2-derived vasoconstrictor agents.