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Targeted deletion of B₂-kinin receptors protects against the development of diabetic nephropathy

¹Department of Medicine, Division of Endocrinology-Diabetes-Medical Genetics, and ²Department of Bioinformatics, Biostatistics and Epidemiology, Medical University of South Carolina, Charleston, South Carolina

Submitted 1 May 2007 ; accepted in final form 18 June 2007

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 B₂-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 B₁-kinin and angiotensin II AT₂ receptors and decreased expression of connective tissue growth factor. At a cellular level, our findings demonstrate that bradykinin downregulates the expression of AT₂ receptors in mesangial cells. These findings provide the first evidence that targeted deletion of B2KR protects against the development of DN.

kinin receptors; albuminuria

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