Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes

The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg(-1) day(-1)) or hydralazine (80 mg kg(-1) day(-1)) for 6 weeks, and the protective effects were extensively compared among groups.All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22(phox)-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg(-1) day(-1)), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2'-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren.Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

肾素抑制对2型糖尿病的影响仍不明确。本研究旨在检测阿利吉仑（一种直接肾素抑制剂）对2型糖尿病小鼠模型中心血管损伤、葡萄糖耐受不良和胰腺损伤的疗效。将患有肥胖症和2型糖尿病的db/db小鼠分组，分别用阿利吉仑（3、6、12和25 mg·kg⁻¹·d⁻¹）或肼屈嗪（80 mg·kg⁻¹·d⁻¹）治疗6周，并在各组之间广泛比较其保护作用。阿利吉仑所有亚降压和降压剂量均显著减轻了db/db小鼠的心脏纤维化、巨噬细胞浸润和冠状动脉重塑，并改善了血管内皮功能。阿利吉仑的这些保护作用归因于其减轻了心脏中与p22phox相关的NADPH氧化酶诱导的超氧化物，并恢复了血管内皮一氧化氮合酶（eNOS）的产生。最高剂量（25 mg·kg⁻¹·d⁻¹）的阿利吉仑，但较低剂量没有，部分减轻了db/db小鼠的葡萄糖耐受不良。此外，最高剂量的阿利吉仑显著减轻了db/db小鼠胰岛胰岛素含量和β细胞数量的减少，并防止了胰岛纤维化，这与阿利吉仑减少胰岛中8 - 羟基 - 2'-脱氧鸟苷阳性细胞和Nox2（也称为Cybb）的表达有关。我们的研究首次提供证据表明，阿利吉仑直接抑制肾素可通过减轻氧化应激来预防心血管并发症和胰腺损伤。因此，我们提出阿利吉仑可能是一种有前途的2型糖尿病治疗药物。