The vasopeptidase inhibitor AVE7688 ameliorates Type 2 diabetic nephropathy

Aim/hypothesis. Pharmacological inhibition of the renin angiotensin system has proven clinical efficacy in nephropathies of various origins, including diabetic nephropathy. We tested the effects of the dual inhibition of both angiotensin converting enzyme and neutral endopeptidase by the vasopeptidase inhibitor AVE7688 in an animal model of Type 2 diabetic nephropathy. Methods. We treated 56 obese Zucker diabetic fatty (ZDF, Gmi-fa/fa) rats aged 34-weeks with either placebo (n = 9) or the vasopeptidase inhibitor AVE7688 in four different doses (each n = 9; 3, 10, 30, or 60 mg/kg/d in chow). We used 11 heterozygous (+/fa) rats which received placebo and served as non-diabetic, lean controls. Urinary albumin/creatinine ratio was assessed as a marker of nephropathy at baseline (age 34-weeks) and after 10 weeks of chronic treatment. Results. All obese animals had established diabetes mellitus that was not influenced by AVE7688 (HbA(1c) >12%, stable in all dose groups). There was massive albuminuria in the homozygous ZDF rats (albumine/creatinine ratio >20 mg/mg vs minimal albuminuria in lean controls) that was decreased by AVE7688 in a dose dependent manner (Placebo 2.0 +/- 4.4 vs 11.9 +/- 1.8, 13.4 +/- 0.7, 13.6 +/- 2.8, and 19.8 +/- 2.8 mg/mg in the 3, 10, 30, and 60 mg/kg/d groups, respectively; all treatment groups p < 0.05 vs Placebo). Conclusion/interpretation. AVE7688 ameliorates proteinuria in Zucker diabetic fatty rats with established diabetes mellitus. Vasopeptidase inhibition represents an effective novel therapeutic principle for intervention in Type 2 diabetic nephropathy independent of metabolic control.