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RAGE Control of Diabetic Nephropathy in a Mouse Model

Effects of RAGE Gene Disruption and Administration of Low–Molecular Weight Heparin

¹ Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
² Department of Clinical Biology and Medicine, School of Medicine, The University of Tokushima, Tokushima, Japan
³ Department of Biochemistry, Faculty of Medicine, University of Toyama, Toyama, Japan
⁴ Department of Biochemistry, Kanazawa Medical University, Ishikawa, Japan
⁵ Department of Anatomy, Kanazawa Medical University, Ishikawa, Japan
⁶ Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa, Japan
⁷ Department of Pathology, Faculty of Medicine, University of Toyama, Toyama, Japan
⁸ Division of Transgenic Animal Science, Kanazawa University Advanced Science Research Center, Kanazawa, Japan
⁹ Department of Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories), Tohoku University Graduate School of Medicine, Sendai, Japan

Address correspondence and reprint requests to Hiroshi Yamamoto, MD, PhD, Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan. E-mail: yamamoto{at}med.kanazawa-u.ac.jp

Abbreviations: AGE, advanced glycation end product; CML, N-carboxymethyl-lysine; CTGF, connective tissue growth factor; ELISA, enzyme-linked immunosorbent assay; ESRD, end-stage renal disease; GAG, glycosaminoglycan; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HUVEC, human umbilical vein endothelial cell; iNOS, inducible nitric oxide synthase; LMWH, low–molecular weight heparin; NFB, nuclear factor-B; PAM, periodic acid-methenamine silver; PAS, periodic acid Schiff; RAGE, receptor for AGEs; siRNA, small interfering RNA; SPR, surface plasmon resonance; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor

Diabetic nephropathy is a major microvascular complication in long-standing diabetic patients who eventually undergo renal dialysis or transplantation. To prevent development of this disease and to improve advanced kidney injury, effective therapies directed toward the key molecular target are required. In this study, we examined whether inhibition of the receptor for advanced glycation end products (RAGE) could attenuate changes in the diabetic kidney. Here, we show that inactivation of the RAGE gene in a mouse model of diabetic nephropathy results in significant suppression of kidney changes, including kidney enlargement, increased glomerular cell number, mesangial expansion, advanced glomerulosclerosis, increased albuminuria, and increased serum creatinine compared with wild-type diabetic mice. The degree of kidney injury was proportional to RAGE gene dosage. Furthermore, we show that low–molecular weight heparin (LMWH) can bind RAGE at a mean equilibrium dissociation constant (K_d) value of 17 nmol/l and act as an antagonist to RAGE. LMWH treatment of mice significantly prevented albuminuria and increased glomerular cell number, mesangial expansion, and glomerulosclerosis in a dose-dependent manner; it also significantly improved the indexes of advanced-stage diabetic nephropathy. This study provides insight into the pathological role of RAGE in both early- and advanced-phase diabetic nephropathy and suggests that RAGE antagonists will be a useful remedy in the treatment of diabetic nephropathy.

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