title: RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin.
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 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 approximately 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.
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
authors.forename: Khin-Mar
authors.initials: KM
authors.lastname: Myint
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kato
authors.forename: Ai
authors.initials: A
authors.lastname: Harashima
authors.forename: Hideto
authors.initials: H
authors.lastname: Yonekura
authors.forename: Takuo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Harumichi
authors.initials: H
authors.lastname: Shinohara
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Shin
authors.initials: S
authors.lastname: Takasawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D006495:Heparin, Low-Molecular-Weight; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic