N-epsilon-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression

Recent studies suggested that interruption of the interaction of advanced g lycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-bin ding domain of RAGE, reversed vascular hyperpermeability and suppressed acc elerated atherosclerosis in diabetic rodents. Since the precise molecular t arget of soluble RAGE in those settings was not elucidated, we tested the h ypothesis that predominant specific AGEs within the tissues in disorders su ch as diabetes and renal failure, N-epsilon-(carboxymethyl)lysine (CML) add ucts, are ligands of RAGE. We demonstrate here that physiologically relevan t CML modifications of proteins engage cellular RAGE, thereby activating ke y cell signaling pathways such as NF-KB and modulating gene expression. Thu s, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inf lammation is an established component.