Abstract
Interaction of advanced glycation end products (AGE) with AGE receptors induces several cellular phenomena potentially relating to diabetic complications. Five AGE receptors identified so far are RAGE (receptor for AGE), galectin-3, 80K-H, OST-48, and SRA (macrophage scavenger receptor class A types I and II). Since SRA is known to belong to the class A scavenger receptor family, and the scavenger receptor collectively represents a family of multiligand lipoprotein receptors, it is possible that CD36, although belonging to the class B scavenger receptor family, can recognize AGE proteins as ligands. This was tested at the cellular level in this study using Chinese hamster ovary (CHO) cells overexpressing human CD36 (CD36-CHO cells). Cellular expression of CD36 was confirmed by immunoblotting and immunofluorescent microscopy using anti-CD36 antibody. Upon incubation at 37 degrees C, (125)I-AGE-bovine serum albumin (AGE-BSA) and (125)I-oxidized low density lipoprotein (LDL), an authentic ligand for CD36, were endocytosed in a dose-dependent fashion and underwent lysosomal degradation by CD36-CHO cells, but not wild-type CHO cells. In binding experiments at 4 degrees C, (125)I-AGE-BSA exhibited specific and saturable binding to CD36-CHO cells (K(d) = 5.6 microg/ml). The endocytic uptake of (125)I-AGE-BSA by these cells was inhibited by 50% by oxidized LDL and by 60% by FA6-152, an anti-CD36 antibody inhibiting cellular binding of oxidized LDL. Our results indicate that CD36 expressed by these cells mediates the endocytic uptake and subsequent intracellular degradation of AGE proteins. Since CD36 is one of the major oxidized LDL receptors and is up-regulated in macrophage- and smooth muscle cell-derived foam cells in human atherosclerotic lesions, these results suggest that, like oxidized LDL, AGE proteins generated in situ are recognized by CD36, which might contribute to the pathogenesis of diabetic macrovascular complications.
Highlights
In the Maillard reaction, proteins react with glucose to form Schiff base and Amadori products
Our previous studies using Chinese hamster ovary (CHO) cells overexpressing the class A scavenger receptor (SRA) [29] and peritoneal macrophages prepared from SRA knockout mice [28] indicated that SRA is one of the major advanced glycation end products (AGE) receptors involved in the endocytic uptake of AGE proteins by macrophages or macrophagederived cells
Nozaki et al [39] demonstrated that the endocytic uptake of oxidized low density lipoprotein (Ox-low density lipoprotein (LDL)) by monocyte-derived macrophages obtained from CD36-deficient patients was reduced by ϳ50% compared with that by macrophages prepared from normal subjects and that the subsequent Ox-LDL-induced accumulation of cholesteryl esters was reduced in CD36-deficient macrophages
Summary
In the Maillard reaction, proteins react with glucose to form Schiff base and Amadori products. The endocytic uptake of 125I-AGE-BSA by these cells was inhibited by 50% by oxidized LDL and by 60% by FA6-152, an anti-CD36 antibody inhibiting cellular binding of oxidized LDL. Our results indicate that CD36 expressed by these cells mediates the endocytic uptake and subsequent intracellular degradation of AGE proteins.
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