Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress.
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.
Vincent
Andrea M
AM
Department of Neurology, Room 5017 BSRB, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109, USA. andreav@umich.edu
Perrone
Lorena
L
Sullivan
Kelli A
KA
Backus
Carey
C
Sastry
Ann Marie
AM
Lastoskie
Christian
C
Feldman
Eva L
EL
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008024:Ligands; D019255:NADPH Oxidases / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D009418:S100 Proteins / Q000494:pharmacology; D015398:Signal Transduction
D017127:Glycation End Products, Advanced; D008024:Ligands; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose