Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats

Background. Recent data suggest that aldosterone antagonistshave beneficial effects on diabetic nephropathy. In this study,we investigated the dose-dependent effect of eplerenone anda combined treatment with eplerenone and enalapril comparedwith each drug alone on renal function in type II diabetic rats.To further explore the molecular mechanism of action of combinationtherapy, we also performed in vitro study. Methods. The animals were divided into six groups as follows:normal control Long-Evans Tokushima Otsuka (LETO) rats, OtsukaLong-Evans Tokushima Fatty (OLETF) rats, OLETF rats treatedwith low dose of eplerenone (50 mg/kg/day), OLETF rats treatedwith high dose of eplerenone (200 mg/kg/day), OLETF rats treatedwith enalapril (10 mg/kg/day) and OLETF rats treated with acombination of both drugs (eplerenone 200 mg/kg/day and enalapril10 mg/kg/day) for 6 months. Results. Treatment of OLETF rats had no significant effect onbody weight, kidney weight and blood glucose levels. However,urinary albumin excretion, glomerular filtration rate and glomerulosclerosiswere significantly improved in the enalapril group and improvementwas observed in a dose-dependent manner in the eplerenone groups;the most dramatic decreases were observed in the combinationgroup. In accordance with these findings, renal expressionsof TGF-β1, type IV collagen and PAI-1 were also markedlydecreased in the treatment groups, with the combined treatmentproviding the most significant level of improvement. In culturedmesangial cells, combined treatment resulted in an additivedecrease in TGF-β1, PAI-1 and collagen gene expressionsand protein production induced by high glucose and aldosteronestimulation. Conclusions. Aldosterone receptor antagonism provided additionalbenefits beyond blockade of the renin–angiotensin systemin type II diabetic nephropathy.