_targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy
- PMID: 17596525
- DOI: 10.1152/ajprenal.00203.2007
_targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy
Abstract
Diabetic nephropathy (DN), the leading cause of end-stage renal failure, is clinically manifested by albuminuria and a progressive decline in glomerular filtration rate. The factors and mechanisms that contribute to progression of DN are still undefined. To address the contribution of B(2)-kinin receptors (B2KR) to the development of DN, we studied B2KR knockout mice (B2KR(-/-)) and their wild-type littermates (B2KR(+/+)). Diabetes was induced by daily injections of streptozotocin (50 mg/kg body wt) for 3-5 days. A total of 48 mice divided into 4 groups were used: group 1, wild-type control (B2KR(+/+) C); group 2, wild-type diabetic (B2KR(+/+) D); group 3, B2KR knockout control (B2KR(-/-) C); and group 4, B2KR knockout diabetic (B2KR(-/-) D). Glucose levels and albumin excretion rate (AER) were measured at predetermined intervals. Half of the mice were killed at 3 mo, and the remaining half, at 6 mo. Plasma glucose levels were markedly elevated in both B2KR(+/+) D and B2KR(-/-) D groups of mice compared with their controls. Diabetic B2KR(-/-) mice displayed reduced AER as well as reduced glomerular and tubular injury compared with diabetic B2KR(+/+) mice. The renoprotection conferred by deletion of B2KR was associated with increased renal expression of B(1)-kinin and angiotensin II AT(2) receptors and decreased expression of connective tissue growth factor. At a cellular level, our findings demonstrate that bradykinin downregulates the expression of AT(2) receptors in mesangial cells. These findings provide the first evidence that _targeted deletion of B2KR protects against the development of DN.
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