DNA Aptamer Raised Against AGEs Blocks the Progression of Experimental Diabetic Nephropathy

  1. Sho-ichi Yamagishi2
  1. 1Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
  2. 2Department of Pathophysiology and Therapeutics of Diabetic Complications, Kurume University School of Medicine, Kurume, Japan
  3. 3Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan
  4. 4Department of Advanced Medicine Medical Research Institute, Kanazawa Medical University, Ishikawa, Japan
  5. 5Department of Chemistry, Keio University School of Medicine, Tokyo, Japan
  1. Corresponding authors: Kei Fukami, fukami{at}med.kurume-u.ac.jp, and Sho-ichi Yamagishi, shoichi{at}med.kurume-u.ac.jp.
  1. Y.K., K.F., and S.-i.Y. contributed equally to this study.

Abstract

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.

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  1. Diabetes vol. 62 no. 9 3241-3250
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