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 recepto rs are: scavenger receptors types I and II, the receptor for advanced glycation endproducts (RAGE), oligosaccharyl transferase-48 (OST-48, A GE-Ri), 80K-H phosphoprotein (AGE-R2) and galectin-3 (AGE-R3). AGE rec eptors are found in monocytes, macrophages, endothelial cells, pericyt es, podocytes, astrocytes and microglia. AGE-modified proteins also bi nd to lysozyme and lactoferrin. A critical review of the evidence for receptors binding AGE-modified protein binding in vivo is presented. S cavenger receptors have only been shown to bind proteins modified by A GE to a much higher extent than found in vivo. 80K-H phosphoprotein is involved in FGFR3 signal transduction to MAP kinase, and may be invol ved 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 expr ession of extracellular matrix proteins, vascular adhesion molecules, cytokines and growth factors. Depending on the cell type and concurren t signaling, this is associated with chemotaxis, angiogenesis, oxidati ve 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 can didates. Pharmacologic inhibition of AGE receptor-mediated cell activa tion with specific antagonists may provide the basis for therapeutic i ntervention in diseases where AGE accumulation is a suspected etiologi cal factor vascular complications of diabetes, macrovascular disease, renal insufficiency and Alzheimer's disease.