RAGE Control of Diabetic Nephropathy in a Mouse Model

RAGE Control of Diabetic Nephropathy in a Mouse Model Effects of RAGE Gene Disruption and Administration of Low–Molecular Weight Heparin Khin-Mar Myint 1 , Yasuhiko Yamamoto 1 , Toshio Doi 2 , Ichiro Kato 3 , Ai Harashima 1 , Hideto Yonekura 1 4 , Takuo Watanabe 1 , Harumichi Shinohara 5 , Masayoshi Takeuchi 6 , Koichi Tsuneyama 7 , Noriyoshi Hashimoto 8 , Masahide Asano 8 , Shin Takasawa 9 , Hiroshi Okamoto 9 and Hiroshi Yamamoto 1 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 Abstract 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 inj