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 glycation end products (AGEs), with the signal-transducing receptor receptor for AGE (RAGE), by administration of the soluble, extracellular ligand-binding domain of RAGE, reversed vascular hyperpermeability and suppressed accelerated atherosclerosis in diabetic rodents. Since the precise molecular target of soluble RAGE in those settings was not elucidated, we tested the hypothesis that predominant specific AGEs within the tissues in disorders such as diabetes and renal failure, N(epsilon)-(carboxymethyl)lysine (CML) adducts, are ligands of RAGE. We demonstrate here that physiologically relevant CML modifications of proteins engage cellular RAGE, thereby activating key cell signaling pathways such as NF-kappaB and modulating gene expression. Thus, CML-RAGE interaction triggers processes intimately linked to accelerated vascular and inflammatory complications that typify disorders in which inflammation is an established component.
Kislinger
T
T
College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Fu
C
C
Huber
B
B
Qu
W
W
Taguchi
A
A
Du Yan
S
S
Hofmann
M
M
Yan
S F
SF
Pischetsrieder
M
M
Stern
D
D
Schmidt
A M
AM
D000818:Animals; D003920:Diabetes Mellitus; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced; D006801:Humans; D008168:Lung / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D051437:Renal Insufficiency; D012709:Serum Albumin / Q000378:metabolism*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012709:Serum Albumin; D019010:Vascular Cell Adhesion Molecule-1; C048496:N(6)-carboxymethyllysine; D008239:Lysine