DNA Aptamer Raised Against AGEs Blocks the Progression of Experimental Diabetic Nephropathy
- Yusuke Kaida1,
- Kei Fukami1⇑,
- Takanori Matsui2,
- Yuichiro Higashimoto3,
- Yuri Nishino2,
- Nana Obara1,
- Yosuke Nakayama1,
- Ryotaro Ando1,
- Maki Toyonaga1,
- Seiji Ueda1,
- Masayoshi Takeuchi4,
- Hiroyoshi Inoue5,
- Seiya Okuda1 and
- Sho-ichi Yamagishi2⇑
- 1Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- 2Department of Pathophysiology and Therapeutics of Diabetic Complications, Kurume University School of Medicine, Kurume, Japan
- 3Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan
- 4Department of Advanced Medicine Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
- 5Department of Chemistry, Keio University School of Medicine, Tokyo, Japan
- Corresponding authors: Kei Fukami, , and Sho-ichi Yamagishi, .
Y.K., K.F., and S.-i.Y. contributed equally to this study.
Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight-week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with those in C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2′-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor, and type IV collagen both in the kidney of KKAy/Ta mice and in AGE-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy.
- Received November 20, 2012.
- Accepted April 21, 2013.
- © 2013 by the American Diabetes Association.
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