Nephroprotection in Zucker diabetic fatty rats by vasopeptidase inhibition is partly bradykinin B2 receptor dependent.
1. Vasopeptidase inhibition (i.e., the simultaneous inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase) can ameliorate diabetic nephropathy. We investigated whether this nephroprotection is mediated by the bradykinin B2 receptor. 2. In all, 43 obese Zucker diabetic fatty (ZDF/Gmi-fa/fa) rats aged 21 weeks were separated into four groups and treated for 26 weeks with either placebo, the bradykinin B2 receptor antagonist icatibant (500 microg kg(-1) day(-1) s.c. infusion), the vasopeptidase inhibitor AVE7688 (45 mg kg(-1) day(-1) in chow), or AVE7688 plus icatibant. Nephropathy was assessed as albuminuria at age 31 and 39 weeks, and by histopathologic scoring at the end of the treatment period. 3. All animals had established diabetes mellitus (blood glucose >20 mmol l(-1)) and marked albuminuria at baseline. Blood glucose was not influenced by any treatment. Icatibant alone did not influence albuminuria (8.6+/-1.6 vs placebo 9.5+/-1.3 mg kg(-1) h(-1)). AVE7688 reduced albuminuria at week 31 markedly to 1.1+/-0.1 mg kg(-1) h(-1) and reduced glomerular and tubulo-interstitial kidney damage at week 47. In the AVE7688 plus icatibant group, proteinuria was significantly higher than in the AVE7688 only group (2.0+/-0.6 mg kg(-1) h(-1)), but still reduced compared to placebo. In addition, icatibant partly antagonized the tubulo-interstitial protection mediated by AVE7688. 4. We conclude that vasopeptidase inhibition provides nephroprotection in rats with type II diabetic nephropathy, which is partly mediated by bradykinin B2 receptor activation.
Disease Group Cardiovascular Diseases, Aventis Pharma Deutschland GmbH, Building H 821, D-65926 Frankfurt am Main, Germany. stefan.schaefer@aventis.com
Stefan
S
Schäfer
Hans-Ludwig
HL
Schmidts
Markus
M
Bleich
Andreas E
AE
Busch
Wolfgang
W
Linz
D000110:Acetylcholinesterase / Q000097:blood; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004435:Eating / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D043782:Receptor, Bradykinin B2 / Q000187:drug effects*
C479877:AVE 7688; D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D006575:Heterocyclic Compounds, 3-Ring; D011480:Protease Inhibitors; D043782:Receptor, Bradykinin B2; C065679:icatibant; D003404:Creatinine; D000110:Acetylcholinesterase; D001920:Bradykinin