Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy.
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.
Tan
Yan
Y
Department of Medicine, Division of Endocrinology-Diabetes-Medical Genetics, Medical University of South Carolina, Charleston, SC 29425, USA.
Keum
Joo-Seob
JS
Wang
Bing
B
McHenry
M Brent
MB
Lipsitz
Stuart R
SR
Jaffa
Ayad A
AA
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D017353:Gene Deletion; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D012709:Serum Albumin / Q000378:metabolism; D013311:Streptozocin
D001786:Blood Glucose; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D012709:Serum Albumin; D055513:Connective Tissue Growth Factor; D013311:Streptozocin