RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin.
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.
Myint
Khin-Mar
KM
Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
Yamamoto
Yasuhiko
Y
Doi
Toshio
T
Kato
Ichiro
I
Harashima
Ai
A
Yonekura
Hideto
H
Watanabe
Takuo
T
Shinohara
Harumichi
H
Takeuchi
Masayoshi
M
Tsuneyama
Koichi
K
Hashimoto
Noriyoshi
N
Asano
Masahide
M
Takasawa
Shin
S
Okamoto
Hiroshi
H
Yamamoto
Hiroshi
H
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*
D017127:Glycation End Products, Advanced; D006495:Heparin, Low-Molecular-Weight; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic