Receptor-mediated interactions of advanced glycosylation end products with cellular components within diabetic tissues.
AGEs are nonenzymatically glycosylated adducts of proteins that accumulate in vascular tissues with aging and at an accelerated rate in people with diabetes; AGEs are closely linked to tissue damage due to their high reactivity in protein cross-linking. A macrophage-monocyte receptor system for AGE moieties is shown to mediate the uptake of AGE-modified proteins by a process that also induces cachectin-TNF, IL-1, IGF-I, and PDGF secretion. Thus, in addition to removing senescent glucose-modified proteins and cells, AGE-mediated release of growth-promoting factors may represent a mechanism by which macrophages signal mesenchymal cells the need for replacement of senescent proteins. The age of the macrophage correlates inversely with the binding and removal capacity of the AGE receptor, possibly preventing the clearance of cross-linked proteins and the compounding aging-related tissue damage. In addition to monocyte and macrophages, other cells express similar receptors for AGE-proteins, including endothelial cells, fibroblasts, and mesangial cells. Endothelial cell AGE-receptors mediate transcytosis of AGEs to the subendothelium, induce increased permeability, and enhance endothelium-dependent procoagulant activity. Renal mesangial AGE receptors mediate PDGF-dependent extracellular matrix protein production. Fibroblast AGE receptors may influence cellular proliferation by EGF and EGF-receptor regulation. These findings, in connection with the known abundance of AGEs in aged and diabetic tissues, indicate that AGE-ligand-receptor interactions are crucial for the development of age- and diabetes-related vascular tissue and renal pathology.
Vlassara
H
H
Picower Institute for Medical Research, Manhasset, New York 11030.
D000375:Aging / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*
D011506:Proteins; D011956:Receptors, Cell Surface