Role of AGE Receptors in Diabetic Complications

蛋白质与葡萄糖的长期孵育通过席夫碱和Amadori产物导致晚期糖基化终产物(AGE)的形成。最近对AGE结构以及AGE受体(AGE受体)的研究强调翻译后AGE修饰参与了衰老和AGE增强型疾病的过程，如糖尿病并发症、动脉粥样硬化和阿尔茨海默病S病。到目前为止，已鉴定出三种AGE受体，如SR-A(清道夫受体A类)、Galectin-3和RAGE(AGE受体)。在本研究中，我们确定了AGE受体在糖尿病并发症发病机制中的意义。用过表达人Galectin-3的CHO细胞进行的体外实验表明，Galectin-3不仅是一种AGE受体，而且还是一种修饰的低密度脂蛋白的受体，它能摄取AGE-BSA、乙酰化低密度脂蛋白和氧化低密度脂蛋白，随后还能降解溶酶体在RAGE项目的基础上，我们成功培育了RAGE转基因小鼠，在心、肾、肝、肺和巨噬细胞中高表达RAGE。他们的生化和形态分析正在进行中。我们先前在1997年发现A类清道夫受体(SR-A)作为AGE受体。这一概念在目前进一步扩展到B类清道夫受体家族，如CD-36和SR-BI。CD-36过表达的CHO细胞显示内吞和随后细胞内AGE蛋白的降解，表明CD36原位识别产生的AGE蛋白，这可能参与糖尿病大血管并发症的发病机制。通过SR-BI过表达的CHO细胞(SR-BI-CHO)，我们清楚地表明SR-BI也是一种AGE受体。此外，SR-BI介导的高密度脂蛋白胆固醇酯的选择性摄取以及高密度脂蛋白介导的胆固醇从SR-BI-CHO细胞中的流出都被AGE配体有效地竞争，表明AGE配体在体内高密度脂蛋白介导的胆固醇反向转运中起着重要的作用。较少

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 … More 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