ACE inhibitor and angiotensin type I receptor antagonist in combination reduce renal damage in obese Zucker rats

Kidney Int. 2004 Jun;65(6):2343-59. doi: 10.1111/j.1523-1755.2004.00661.x.


Background: In this study, we evaluated whether a combination of an angiotensin-converting enzyme (ACE) inhibitor, benazepril (B), with an angiotensin type I receptor antagonist (AT1RA), irbesartan (I), is as effective or more than drugs as monotherapy in controlling renal damage in obese Zucker rats (OZR), a model of metabolic syndrome.

Methods: During six months, G1 (OZR receiving no treatment); G2 (OZR with B 10 mg/kg/day); G3 (OZR with I 50mg/kg/day); and G4 (OZR with B 5mg/kg/day + I 25 mg/kg/day). Kidneys were processed for light microscopy (LM) and immunohistochemistry, including antibodies against interstitial alpha-smooth-muscle-actin (alpha-SMA), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-beta(1)(TGF-beta 1), and collagen (COL) I, III, and IV.

Results: All treated groups presented similar reduction in blood pressure compared with untreated OZR. However, animals from G4 (B + I) showed better control on proteinuria together with a higher creatinine clearance. Additionally, G4 showed a significant (P < 0.05) lower kidney weight; smaller glomerular area; lower glomerulosclerosis score; lower percentage of tubular atrophy, interstitial fibrosis, and interstitial alpha-SMA; lower tubular PAI-1 score; lower percentage of COL I, III, and IV in renal interstitium; and lower wall/lumen ratio in renal vessels, when compared with the other groups. OZR treated with B and/or I showed a better outcome (P < 0.01) in the carbohydrate and lipid metabolism in comparison with untreated OZR.

Conclusion: These results suggest that combined therapy using B and I is more effective than therapy with either drug at monotherapy for controlling renal damage in this animal model. In addition, data presented here reaffirm the benefit of interacting against renin-angiotensin-system (RAS) in the metabolic syndrome.

MeSH terms

  • Actins / metabolism
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage*
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage*
  • Animals
  • Benzazepines / administration & dosage
  • Biphenyl Compounds / administration & dosage
  • Collagen / metabolism
  • Drug Therapy, Combination
  • Irbesartan
  • Kidney / drug effects*
  • Kidney / pathology
  • Kidney / physiopathology
  • Male
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / pathology
  • Metabolic Syndrome / physiopathology
  • Obesity / drug therapy
  • Obesity / pathology
  • Obesity / physiopathology
  • Organ Size / drug effects
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Rats
  • Rats, Zucker
  • Tetrazoles / administration & dosage
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1


  • Actins
  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Benzazepines
  • Biphenyl Compounds
  • Plasminogen Activator Inhibitor 1
  • Tetrazoles
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Collagen
  • Irbesartan
  • benazepril