RAGE control of diabetic nephropathy in a mouse model: Effects of RAGE gene disruption and administration of low-molecular weight heparin

Khin Mar Myint, Yasuhiko Yamamoto, Toshio Doi, Ichiro Kato, Ai Harashima, Hideto Yonekura, Takuo Watanabe, Harumichi Shinohara, Masayoshi Takeuchi, Koichi Tsuneyama, Noriyoshi Hashimoto, Masahide Asano, Shin Takasawa, Hiroshi Okamoto, Hiroshi Yamamoto

Research output: Contribution to journalArticlepeer-review

183 Citations (Scopus)

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 (Kd) 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.

Original languageEnglish
Pages (from-to)2510-2522
Number of pages13
JournalDiabetes
Volume55
Issue number9
DOIs
Publication statusPublished - 2006 Sep

Keywords

  • AGE, advanced glycation end product
  • CML, N{varepsilon}-carboxymethyl- lysine
  • CTGF, connective tissue growth factor
  • ELISA, enzyme-linked immunosorbent assay
  • ESRD, end-stage renal disease
  • GAG, glycosaminoglycan

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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