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Receptor for Advanced Glycation End Products Activation Injures Primary Sensory Neurons via Oxidative Stress

Departments of Neurology (A.M.V., L.P., K.A.S., C.B., E.L.F.), Mechanical Engineering (A.M.S.), Biomedical Engineering (A.M.S., C.L.), and Civil and Environmental Engineering (C.L.), University of Michigan, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Andrea M. Vincent, Ph.D., Department of Neurology, Room 5017 BSRB, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109. E-mail: andreav{at}umich.edu.

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 -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.

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