ET and Diabetic Nephropathy: Preclinical and Clinical Studies

The incidence of progressive kidney disease associated with diabetes continues to increase worldwide. Only partial renoprotection is achieved by current standard therapy with angiotensin-converting enzyme inhibitors and/or angiotensin-receptor blockers, increasing the need for novel therapeutic approaches. Experimental studies have provided evidence of a pathogenic role for endothelin-1 (ET-1) and its cognate receptors in the development and progression of diabetic nephropathy. ET-1, mainly through the activation of ET_A receptor, contributes to renal cell injury, inflammation, and fibrosis. In animal models of type 1 and type 2 diabetes, ET_A-selective antagonists have been shown to provide renoprotective effects, supplying the rationale for clinical trials in patients with diabetic nephropathy with ET_A-receptor antagonists administered in addition to renin-angiotensin system blockade.