RENOPROTECTIVE EFFECTS OF DUAL BLOCKADE OF RENIN-ANGIOTENSIN SYSTEM WITH CANDESARTAN AND PERINDOPRIL IN STREPTOZOTOCIN INDUCED DIABETIC NEPHROPATHY

Abstract

Introduction. Renin-angiotensin system (RAS) inhibition exerts a renoprotective effect independent of blood pressure reduction. Several studies suggest that combination therapy with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARBs) provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAS inhibition. The aim of the present study was to determine if a combination therapy with perindopril and candesartan at lower doses than monotherapy would confer greater renoprotection in streptozotocin (STZ) induced diabetic nephropathy. Methods. Wistar rats (n=125) were used in this study. Diabetes was induced by a single i.p. injection of STZ (60 mg/kg). The diabetic rats (n=100) were randomly assigned to receive vehicle, ARB-Candesartan (5 mg/kg/per d), ACE-I -Perindopril (6 mg/kg/per d), or a combination of low dose Candesartan+Perindopril (2,5 mg/kg/per d and 3 mg/kg/ per d) respectively, from weeks 4-12. Pathological changes of the kidney were examined with optical and transmission electron microscope.Results. Albumin excretion rate, kidney/body weight ratio and renal structural changes increased significantly in untreated diabetic rats compared to normal control rats. Treatment with candesartan, perindopril, or both decreased these changes. Addition of the candesartan to perindopril was more effective in reducing renal structural changes and improvement of renal function than monotherapy with either drug. Conclusion. Combination therapy has the additional benefit of requiring only low doses of ACE-I and ARBs to achieve superior renoprotective effects in this diabetic nephropathy model, possibly due to dual inhibitory effect on the RAS.