gms | German Medical Science

Inhibition of the renin angiotensin aldosterone system (RAAS) has protective effects on cardio-renal injury in type II diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type II diabetes in comparison to angiotensin converting enzyme inhibition (ACE-I). Zucker Diabetic Fatty (ZDF) rats aged 13 weeks were treated with either VPI (AVE7688 30 mg/kg/d, ZDF-VPI, n=8) or ACE-I (Ramipril 1 mg/kg/d, ZDF-ACE-I, n=7) or placebo (ZDF, n=8). Heterozygous rats served as non-diabetic controls (Ctr, n=8). Blood pressure was measured weekly. Urinary albumin excretion was analysed by ELISA. Both treatments led to a similar decrease of blood pressure. After 10 weeks of treatment, there was a marked albuminuria in ZDF (58,8 mg/d vs Ctr 0.5,0.3 mg/d, p<0.001) and ZDF-ACE-I (36,7 mg/d, p<0.005 vs Ctr) rats. In contrast, albuminuria in ZDF-VPI was significantly attenuated (14,4 mg/d, p<0.001 vs ZDF). Renal histology revealed a significant expansion in glomerular tuft area in diabetic animals (12557,243 µm2 vs Ctr 9105,209 µm2 p<0.001) which was not influenced by either treatment. However, de-novo expression of glomerular desmin, which is a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to non diabetic rats (desmin positive glomerular tuft area: Ctr 3.0,0.3% vs ZDF 19,2.9 %, p<0.001). Desmin expression was reduced in animals treated with VPI (ZDF+VPI 10 - 1.4%, p<0.05 vs ZDF), but not in animals treated with ACE-I (ZDF+ACE-I 26,3.4 %, p=n.s.). There was a strong correlation between albumin excretion and desmin positive glomerular area. In experimental type II diabetes, albuminuria is closely correlated to podocyte damage which is attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest podocyte damage as an early critical step in the progression of diabetic nephropathy and VPI as a promising pharmacological tool in the treatment of diabetic renal disease.