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


CONCLUSIONS
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.
Toblli
Jorge Eduardo
JE
Laboratory of Experimental Medicine, Hospital Alemán, CONICET, Buenos Aires, Argentina. jtoblli@hospitalaleman.com
DeRosa
Graciela
G
Cao
Gabriel
G
Piorno
Pablo
P
Pagano
Patricia
P
D000199:Actins / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D003094:Collagen / Q000378:metabolism; D004359:Drug Therapy, Combination; D000077405:Irbesartan; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009765:Obesity / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013777:Tetrazoles / Q000008:administration & dosage; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D001713:Biphenyl Compounds; D017395:Plasminogen Activator Inhibitor 1; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D000077405:Irbesartan; C044946:benazepril