Nephroprotection in Zucker diabetic fatty rats by vasopeptidase inhibition is partly bradykinin B2 receptor dependent

• Published in: British journal of pharmacology Vol. 143; no. 1; pp. 27 - 32
• Main Authors: Schäfer, Stefan, Schmidts, Hans‐Ludwig, Bleich, Markus, Busch, Andreas E, Linz, Wolfgang
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2004; Nature Publishing
• Subjects: Acetylcholinesterase - blood; Adrenergic beta-Antagonists - pharmacology; Aging - physiology; Animals; AVE7688; Biological and medical sciences; Blood Glucose - metabolism; Blood Vessels - drug effects; Blood Vessels - enzymology; Body Weight - drug effects; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Creatinine - blood; Creatinine - urine; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - prevention & control; diabetic nephropathy; Eating - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Hemodynamics - drug effects; Heterocyclic Compounds, 3-Ring - pharmacology; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney Function Tests; Male; Medical sciences; Pharmacology. Drug treatments; Protease Inhibitors - pharmacology; Rats; Rats, Zucker; Receptor, Bradykinin B2 - drug effects; vasopeptidase inhibition; Zucker diabetic fatty rat; Endocrinopathy; Kidney disease; Urinary system disease; Rat; Diabetes mellitus; Rodentia; B2 bradykinin receptor; Vertebrata; Mammalia; AVE7688; Zucker diabetic fatty rat; Animal; vasopeptidase inhibition; Diabetic nephropathy
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705884

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. 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 μg 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. 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. We conclude that vasopeptidase inhibition provides nephroprotection in rats with type II diabetic nephropathy, which is partly mediated by bradykinin B2 receptor activation. British Journal of Pharmacology (2004) 143, 27–32. doi:10.1038/sj.bjp.0705884