Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress

Endocrinology. 2007 Feb;148(2):548-58. doi: 10.1210/en.2006-0073. Epub 2006 Nov 9.


The receptor for advanced glycation end products (RAGE) may promote diabetic vascular and renal disease through the activation of intracellular signaling pathways that promote oxidative stress. Oxidative stress is a mediator of hyperglycemia-induced cell injury and a unifying theme for all mechanisms of diabetic complications, but there are few studies on the expression and potential contribution of RAGE in diabetic neuropathy. The current study demonstrates that dorsal root ganglia neurons express functional RAGE and respond to the RAGE ligand S100 with similar downstream signaling, oxidative stress, and cellular injury as other diabetic complication-prone tissues. RAGE-induced phosphatidylinositol-3 kinase activity is associated with formation of reactive oxygen species, caspase-3 activation, and nuclear DNA degradation. These events are prevented by treatment with the antioxidant alpha-lipoic acid. Our data indicate that therapies aimed at decreasing RAGE ligands, blocking RAGE signaling, or preventing oxidative stress could significantly decrease the development of neuropathy in diabetic patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Glucose / administration & dosage
  • Glucose / pharmacology
  • Glycation End Products, Advanced / metabolism
  • Intracellular Membranes / metabolism
  • Ligands
  • NADPH Oxidases / metabolism
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism*
  • Neurons, Afferent / pathology*
  • Oxidative Stress*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*
  • S100 Proteins / pharmacology
  • Signal Transduction


  • Glycation End Products, Advanced
  • Ligands
  • Reactive Oxygen Species
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • S100 Proteins
  • NADPH Oxidases
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose