CELLULAR RECEPTORS FOR ADVANCED GLYCATION END-PRODUCTS - IMPLICATIONSFOR INDUCTION OF OXIDANT STRESS AND CELLULAR DYSFUNCTION IN THE PATHOGENESIS OF VASCULAR-LESIONS

Advanced glycation end products (AGEs) form by the interaction of aldo ses with proteins and the subsequent molecular rearrangements of the c ovalently linked sugars, eventuating in a diverse group of fluorescent compounds of yellow-brown color. This heterogeneous class of nonenzym atically glycated proteins or lipids is found in the plasma and accumu lates in the vessel wall and tissues even in normal aging. As a conseq uence of hyperglycemia, AGE formation and deposition are much enhanced in diabetes, in which their presence has been linked to secondary com plications, especially microvascular disease. This review summarizes t he cellular interactions of AGEs and describes the central role of a n ovel receptor for AGE (RAGE). RAGE, an immunoglobulin superfamily memb er, mediates the binding of AGEs to endothelial cells and mononuclear phagocytes, interacts with a lactoferrin-like polypeptide that also bi nds AGEs, and appears to activate intracellular signal transduction me chanisms consequent to its interaction with the glycated ligand. RAGE is expressed by ECs, mononuclear phagocytes, smooth muscle cells, mesa ngial cells, and neurons, indicating a potential role in the regulatio n of their properties in homeostasis and/or their dysfunction in the d evelopment of diabetic complications. Since AGEs have been shown to ge nerate reactive oxygen intermediates, tethering of AGEs to the cell su rface by their receptors focuses oxidant stress on cellular targets, r esulting in changes in gene expression and the cellular phenotype. The discovery of RAGE and development of reagents to block its interactio n with AGEs should provide insights into the role of this ligand-recep tor interaction in the pathogenesis of diabetic complications and, pot entially, atherosclerosis.