| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2000: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 1999: ¥8,300,000 (Direct Cost: ¥8,300,000)
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| Research Abstract |
Long-term incubation of proteins with glucose leads, through the Schiff base and Amadori product, to the formation of advanced glycation end products (AGE). Recent studies of AGE-structures as well as the receptors for AGE (AGE-receptors) have emphasized the involvement of post-translational AGE-modification in aging and age-enhanced disease processes such as diabetic complications, atheroscleorosis and Alzheimer s disease. Three AGE receptors such as SR-A (scavenger receptor class A), galectin-3 and RAGE (receptor for AGE) have so far been identified. In the present study, we determined the significance of AGE receptors in the pathogenesis of diabetic complications. In vitro experiments using CHO cells overexpressed with human galectin-3 demonstrated endocytic uptake of ^<125>-AGE-BSA, acetylated-low density lipoprotein (LDL) and oxidized LDL, followed by lysosomal degradation, indicating that galectin-3 serves not only as an AGE-receptor but also as a receptor for modified LDL.Regard
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ing to the RAGE project, we successfully developed RAGE-transgenic mice, which highly expressed mouse RAGE in heart, kidney, liver, lung and macrophages. Their biochemical and morphological analyses are under way.
We previously discovered classA scavenger receptor (SR-A) serves as AGE-receptor in 1997. This notion was further extended in the present to class B scavenger receptor family such as CD-36 and SR-BI.CD-36-overexpressed CHO cells showed endocytic uptake and subsequent intracellular degradation of AGE-proteins, suggesting that AGE-protein generated in situ are recognized by CD36, which might contribute to the pathogenesis of diabetic macrovascular complications. By using SR-BI-overexpressed CHO cells (SR-BI-CHO), we clearly showed that SR-BI also serves as an AGE receptor. Furthermore, SR-BI-mediated selective uptake of cholesteryl esters of HDL as well as HDL-mediated cholesterol efflux from SR-BI-CHO cells were effectively competed for by AGE-ligands, indicating that AGE-ligands play a significant role in HDL-mediated reverse cholesterol transport in vivo. Less
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