GW24-e3848 The organ protective effect of direct renin inhibitor in a mouse model of type 2 diabetes

Objectives The benefit of blocking the renin-angiotensin system (RAS) with conventional RAS blockers in cardiovascular diseases and nephropathy of patients with type 2 diabetes is now well established. Direct renin inhibitor (DRI) as a novel renin-angiotensin system inhibitor has been used in hypertensive patients. However, the efficacy of DRI in type 2 diabetes has not been fully established. In this study, we firstly investigated the protective effect of aliskiren in a mouse model of type 2 diabetes. Methods Groups of db/db mice (C57BLKS/J-leprdb/leprdb), a mouse model of obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg/kg/day) or hydralazine (80 mg/kg/day) for 6 weeks, and non-diabetic db/m mice (C57BLKS/J-leprdb/+) were used as control. The protective effects were extensively compared among groups. Results Except the lowest dose of aliskiren group, the other doses of aliskiren significantly decreased the blood pressure (BP) of db/db mice. All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, cardiac macrophage infiltration, coronary remodelling, albuminuria, renal glomerulus sclerosis, renal macrophage infiltration and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22phox-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase production. Aliskiren at the highest dose partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis, being associated with the reduction of 8-hydroxy-2’-deoxyguanosine-positive cells and Nox2 expression in pancreatic islets. However, hydralazine showing the same antihypertensive effect as the highest dose of aliskiren did not exert the same protective effect as aliskiren in db/db mice. Conclusions Our work provides the first evidence that direct renin inhibition protects against cardiovascular and renal complications and pancreatic injury in type 2 diabetes, through the attenuation of oxidative stress.