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

¹ Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
² Department of Cell Pathology, Postgraduate School of Medicine, Kumamoto University, Kumamoto, Japan
³ Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
⁴ Laboratory for System Biology and Medicine, The Research Center for Advanced Science and Technology, the University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Kenichi Shikata, MD, PhD, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: shikata{at}md.okayama-u.ac.jp

Abbreviations: AGE, advanced glycation end product; FBS, fetal bovine serum; HUVEC, human umbilical vein endothelial cell; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; mAb, monoclonal antibody; MMI, mesangial matrix index; NIH, National Institutes of Health; OPN, osteopontin; PAM, periodic acid-methenamine silver; PMA, phorbol myristate acetate; RAGE, receptor for AGE; SR-A, scavenger receptor-A; TBS, Tris-buffered saline; TGF, transforming growth factor; UACR, urinary albumin–to–creatinine ratio

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-ß 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 microarray 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.

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