Macrophage Scavenger Receptor-A-Deficient Mice Are Resistant Against Diabetic Nephropathy Through Amelioration of Microinflammation.

Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A^-/-) mice. Diabetes was induced in SR-A^-/- and wild-type (SR-A^+/+) mice by streptozotocin injection. Diabetic SR-A^+/+ mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-β at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A^-/- mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A^-/- mice compared with diabetic SR-A^+/+ mice. DNA micro-array revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A^+/+ mice and suppressed in diabetic SR-A^-/- mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications. Diabetes 56:363-372, 2007 [ABSTRACT FROM AUTHOR]