Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response

Abstract

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.

The ligand-RAGE axis- initiation and potentiation of pancreatic β-cell damage: from autoimmunity to diabetic complications

RAGE was first discovered as a signal transduction receptor for Advanced Glycation Endproducts (AGEs). The identification of RAGE’s multi-ligand nature, and its intimate role in the inflammatory response, however, places RAGE at multiple points in the pathogenesis of type 1 diabetes – and its end-organ damage. (Auto)immune attack at the pancreatic β-cell leads to infiltration of inflammatory cells and increased expression/release of S100/calgranulins and HMGB1. Such ligands target RAGE in the islet and contribute to destruction and, ultimately, hyperglycemia. Hyperglycemia triggers rapid generation of AGEs, thereby recruiting RAGE in target organs via the micro- and macrovasculature. One component of RAGE’s action in target organs is the infiltration of inflammatory cells as well as end-organ stress – processes leading to release of S100/calgranulin and HMGB1. These ligands, together with AGEs, damage such cells as podocytes, endothelial and smooth muscle cells, Muller cells of the retina, cardiomyocytes, and central and peripheral nervous system neurons. Chronic inflammatory signaling, may, we predict, feed back to further damage the pancreatic islet and eliminate the possibility of regeneration. Stopping the cycle of RAGE action in inflammation and diabetes may be a novel form of therapy in this disorder and its complications.