Bradykinin B2 receptors--a target in diabetic nephropathy.
Diabetic nephropathy is the leading cause of chronic renal failure in westernized countries. The polymorphism in angiotensin-converting enzyme (ACE), which leads to higher than normal levels of this enzyme, is a predictor of nephropathy in patients with diabetes. As increasing the levels of ACE by approximately 50% in this polymorphism is only calculated to increase the levels of angiotensin II by < 5%, whereas the levels of bradykinin will decrease by 20%, bradykinin may be nephroprotective. In diabetic mice without bradykinin B2 receptors, the only parameter that is altered compared with the diabetic mouse, is that the nephropathy is worse. Thus, in diabetic mice without a bradykinin receptor (Bdrb2(-/-)Ins2(+/C96Y)), compared with diabetic mice (Bdrb2(+/+)/Ins2(+/C96Y)), there is a greater kidney weight, increased urinary albumin output, and glomeruli mesangial sclerosis. In addition to reducing the levels of angiotensin II, vasopeptidase inhibitors increase the level of bradykinin. A vasopeptidase inhibitor (AVE7688) has been shown to prevent nephropathy developing and to ameliorate it once it has developed in Zucker diabetic rats. The nephroprotective effects (reduced albumin secretion and reduced kidney damage) of AVE7688 in Zucker diabetic rats were partially prevented by the bradykinin B2 receptor antagonist icatibant. These data establish that stimulation of bradykinin B2 receptors is a target in diabetic nephropathy.
Doggrell
Sheila A
SA
The University of Queensland, School of Biomedical Sciences, QLD 4072, Australia. s_doggrell@yahoo.com
D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000378:metabolism; D011480:Protease Inhibitors / Q000008:administration & dosage; D043782:Receptor, Bradykinin B2 / Q000819:agonists* / Q000378:metabolism*
D011480:Protease Inhibitors; D043782:Receptor, Bradykinin B2