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RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions
Authors:Andrew R. Chandna  Manoj Nair  Christine Chang  Paul R. Pennington  Yasuhiko Yamamoto  Darrell D. Mousseau  Verónica A. Campanucci
Affiliation:1. Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada;2. Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada;3. Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
Abstract:Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation‐mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co‐treatment with either antioxidants or an anti‐RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock‐out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes.
Keywords:autonomic neuropathy  diabetes  nicotinic receptors  oxidative stress  RAGE knock‐out mice  sympathetic neurons
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