Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs.
Proteins modified by advanced glycation endproducts (AGE) bind to cell surface receptors and other AGE binding proteins. AGE-binding receptors are: scavenger receptors types I and II, the receptor for advanced glycation endproducts (RAGE), oligosaccharyl transferase-48 (OST-48, AGE-R1), 80K-H phosphoprotein (AGE-R2) and galectin-3 (AGE-R3). AGE receptors are found in monocytes, macrophages, endothelial cells, pericytes, podocytes, astrocytes and microglia. AGE-modified proteins also bind to lysozyme and lactoferrin. A critical review of the evidence for receptors binding AGE-modified protein binding in vivo is presented. Scavenger receptors have only been shown to bind proteins modified by AGE to a much higher extent than found in vivo. 80K-H phosphoprotein is involved in FGFR3 signal transduction to MAP kinase, and may be involved in AGE-receptor signal transduction. Whether all of these proteins bind AGE-modified proteins in vivo is not yet clear. Cell activation in response to AGE-modified proteins is associated with increased expression of extracellular matrix proteins, vascular adhesion molecules, cytokines and growth factors. Depending on the cell type and concurrent signaling, this is associated with chemotaxis, angiogenesis, oxidative stress, cell proliferation or programmed cell death (PCD). Receptor recognition factors for agonism at the AGE receptor have been little studied but to date hydroimidazolones appear to be the most likely candidates. Pharmacologic inhibition of AGE receptor-mediated cell activation with specific antagonists may provide the basis for therapeutic intervention in diseases where AGE accumulation is a suspected etiological factor vascular complications of diabetes, macrovascular disease, renal insufficiency and Alzheimer's disease.
Thornalley
P J
PJ
Department of Biological Sciences, University of Essex, Colchester, UK.
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000145:classification* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic