Renin is the rate-limiting enzyme of the reninangiotensin system (RAS). In addition to its enzymatic activity to generate angiotensin I, renin also signals through the (pro)renin receptor to exert angiotensin II-independent effects. In this study we examined the effect of renin inhibition on the development of diabetic nephropathy. Male DBA/2J mice were induced to diabetes with streptozotocin, and the diabetic mice were treated for 16 weeks with saline or aliskiren, a renin enzymatic inhibitor. Aliskiren treatment had little effects on blood glucose and blood pressure in diabetic mice. Saline-treated mice developed progressive albuminuria and glome-rulosclerosis, and aliskiren treatment effectively alleviated albumiuria and glomerulosclerosis. Morphologically aliskiren treatment prevented the thickening of the glomerular basement membrane and reduced podocyte loss. At the molecular levels, aliskiren prevented the decline of slit diaphragm proteins and blocked the synthesis of extracellular matrix and pro-fibrotic factors in the diabetic kidney. Aliskiren treatment results in compensatory renin increase in the glomeruli due to blockade of the negative feedback loop, and also partially suppressed the intracellular signaling mediated by the (pro)renin receptor activated in hyperglycemia. These observations suggest that the therapeutic activity of aliskiren to prevent diabetic renal injury is contributed by inhibition of both the angiotensin II-dependent and -independent pathways. Taken together, it is concluded that inhibition of renin enzymatic activity ameliorates diabetic renal injury in type 1 diabetes, and support the use of aliskiren in diabetes kidney disease.
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