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.