High-affinity-receptor-mediated uptake and degradation of glucose-modified proteins: a potential mechanism for the removal of senescent macromolecules.
Proteins that have been modified by long-term exposure to glucose accumulate advanced glycosylation end products (AGE) as a function of protein age. In these studies, we have characterized the interaction of AGE-protein with mouse peritoneal macrophages, using AGE-modified bovine serum albumin (AGE-BSA, prepared by incubation with glucose) as a probe. AGE-BSA was specifically bound to cells at 4 degrees C and was taken up and degraded at 37 degrees C; these processes were concentration dependent and saturable. Competition experiments with AGE-BSA, BSA incubated with phosphate-buffered saline rather than glucose, and yeast mannan demonstrated that macrophages specifically recognize AGE on proteins by a receptor that is completely distinct from the mannose/fucose receptor. Scatchard analysis of AGE-BSA binding data indicated that there are approximately 1.06 X 10(5) receptors per macrophage, with an affinity constant of 1.75 X 10(-11) M. Specific binding of AGE-BSA to the macrophage receptor was competitively inhibited by BSA that had been chemically coupled to a synthetic analogue of the specific AGE, 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole (FFI-BSA). FFI-BSA was also taken up by macrophages in a concentration-dependent, saturable manner. Prior incubation of macrophages with AGE-BSA failed to influence the subsequent uptake and degradation of added AGE-BSA. Thus, the AGE receptor does not appear to be down-regulated by exposure to AGE-proteins. Results from these studies suggest that AGE could act in vivo as a specific signal for recognition and degradation of senescent macromolecules. Incomplete removal of AGE-proteins by macrophages may ultimately give rise to some of the physiologic changes that occur with normal aging.
Vlassara
H
H
Brownlee
M
M
Cerami
A
A
D000375:Aging; D000818:Animals; D001667:Binding, Competitive; D005947:Glucose; D006023:Glycoproteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010587:Phagocytosis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000031:analogs & derivatives
D006023:Glycoproteins; D011956:Receptors, Cell Surface; D012710:Serum Albumin, Bovine; D005947:Glucose