Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response.
The actors in the pathogenesis of diabetes and its complications are many and multifaceted. The effects of elevated levels of glucose are myriad; among these is the generation of advanced glycation end products (AGEs), the products of nonenzymatic glycoxidation of proteins and lipids. The finding that AGEs stimulate signal transduction cascades through the multiligand receptor RAGE unveiled novel insights into diabetes and its complications. Inextricably woven into AGE-RAGE interactions in diabetes is the engagement of the innate and adaptive immune responses. Although glucose may be the triggering stimulus to draw RAGE into diabetes pathology, consequent cellular stress results in release of proinflammatory RAGE ligands S100/calgranulins and HMGB1. We predict that once RAGE is engaged in the diabetic tissue, a vicious cycle of ligand-RAGE perturbation ensues, leading to chronic tissue injury and suppression of repair mechanisms. Targeting RAGE may be a beneficial strategy in diabetes, its complications, and untoward inflammatory responses.
Yan
Shi Fang
SF
Department of Surgery, Columbia University, New York, NY 10032, USA.
Ramasamy
Ravichandran
R
Schmidt
Ann Marie
AM
D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D008954:Models, Biological; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction
D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D039841:Leukocyte L1 Antigen Complex; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins