Key pathways in renal disease progression of experimental diabetes

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. Both diabetes and chronic kidney disease are risk factors for cardiovascular disease, and diabetic patients with renal involvement are three times more likely to eventually die of cardiovascular disease than diabetic patients without signs of renal failure. In type 2 diabetes, microalbuminuria is a marker of renal dysfunction and a crucial predictor of cardiovascular disease. Inhibitors of angiotensin II synthesis/activity, while preventing micro- or macroalbuminuria, also reduced cardiovascular events in diabetic patients. However, the effectiveness of renin angiotensin system blocking agents depends on the time when treatment is started, and imperfect renoprotection may occur if therapy begins at an advanced disease phase. This raises the need to identify novel multidrug approaches that simultaneously inhibit additional pathways other than angiotensin II for those diabetic patients who remain at high risk of both poor renal and cardiovascular outcomes. Studies in animal models of diabetes have contributed to defining relevant cellular mechanisms underlying the pathogenesis of DN that could represent possible targets for therapies. The pathogenesis of DN is multifactorial, involving a complex series of molecular processes. In this review, we report evidence obtained in experimental models of DN on some specific processes and pathways implicated in DN that may be crucial for managing this disease.