Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions.
Advanced glycation end products (AGEs) form by the interaction of aldoses with proteins and the subsequent molecular rearrangements of the covalently linked sugars, eventuating in a diverse group of fluorescent compounds of yellow-brown color. This heterogeneous class of nonenzymatically glycated proteins or lipids is found in the plasma and accumulates in the vessel wall and tissues even in normal aging. As a consequence of hyperglycemia, AGE formation and deposition are much enhanced in diabetes, in which their presence has been linked to secondary complications, especially microvascular disease. This review summarizes the cellular interactions of AGEs and describes the central role of a novel receptor for AGE (RAGE). RAGE, an immunoglobulin superfamily member, mediates the binding of AGEs to endothelial cells and mononuclear phagocytes, interacts with a lactoferrin-like polypeptide that also binds AGEs, and appears to activate intracellular signal transduction mechanisms consequent to its interaction with the glycated ligand. RAGE is expressed by ECs, mononuclear phagocytes, smooth muscle cells, mesangial cells, and neurons, indicating a potential role in the regulation of their properties in homeostasis and/or their dysfunction in the development of diabetic complications. Since AGEs have been shown to generate reactive oxygen intermediates, tethering of AGEs to the cell surface by their receptors focuses oxidant stress on cellular targets, resulting in changes in gene expression and the cellular phenotype. The discovery of RAGE and development of reagents to block its interaction with AGEs should provide insights into the role of this ligand-receptor interaction in the pathogenesis of diabetic complications and, potentially, atherosclerosis.
Schmidt
A M
AM
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032.
Hori
O
O
Brett
J
J
Yan
S D
SD
Wautier
J L
JL
Stern
D
D
D000818:Animals; D003920:Diabetes Mellitus / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008955:Models, Cardiovascular; D009000:Monocytes / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014652:Vascular Diseases / Q000209:etiology*
D017127:Glycation End Products, Advanced; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface