Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis

J Mol Cell Cardiol. 2007 Oct;43(4):455-64. doi: 10.1016/j.yjmcc.2007.07.044. Epub 2007 Jul 21.


The receptor for advanced glycation end products (RAGE) and the angiotensin II type I receptor (AT1R) have been separately linked to the pathogenesis of diabetic atherosclerosis. However, no prior study has addressed a linkage between RAGE and AT1R in diabetic atherogenesis. Therefore, we tested the hypothesis that upregulation of the ligand-RAGE axis via AT1R is an essential process underlying the disease. Diabetes was induced in apolipoprotein E-deficient (ApoE(-/-)) mice by streptozotocin, and diabetic mice were treated with AT1 receptor blocker (ARB) for 6 weeks. Diabetic ApoE(-/-) mice that were AT1R-deficient (ApoE(-/-)AT1aR(-/-)) were also investigated. In diabetic ApoE(-/-) mice, AT1R was found to increase within 1 week of diabetes induction, before ligand-RAGE pathway activation and other inflammatory changes were observed. Both ARB treatment and AT1aR deficiency suppressed diabetic atherosclerosis, ligand-RAGE expression and inflammatory changes. In contrast, upregulation of the ligand-RAGE pathway was noted in atherosclerotic plaques from non-diabetic ApoE(-/-) mice infused with angiotensin II. In cultured vascular smooth muscle cells, angiotensin II increased RAGE protein levels via AT1R stimulation. Upregulation of the ligand-RAGE pathway via AT1R is an essential mechanism in diabetic atherosclerosis, implying that ARB might decrease diabetic atherogenesis by inhibiting ligand-RAGE signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Apolipoproteins E / genetics
  • Blood Pressure / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism
  • Coronary Artery Disease / pathology
  • Coronary Artery Disease / physiopathology
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Angiopathies / genetics*
  • Diabetic Angiopathies / metabolism
  • Diabetic Angiopathies / pathology
  • Diabetic Angiopathies / physiopathology
  • Glycation End Products, Advanced / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Rats
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics*
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology
  • Signal Transduction / genetics
  • Up-Regulation


  • Adaptor Proteins, Signal Transducing
  • Agtrap protein, mouse
  • Angiotensin II Type 1 Receptor Blockers
  • Apolipoproteins E
  • Glycation End Products, Advanced
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic