Role of AGE Receptors in Diabetic Complications

蛋白质与葡萄糖的长期孵育通过Schiff碱和Amadori产物导致晚期糖基化终产物（AGE）的形成。近年来对AGE结构及其受体（AGE-受体）的研究强调了AGE的翻译后修饰在衰老和年龄增强的疾病过程（如糖尿病并发症、动脉粥样硬化和阿尔茨海默病）中的作用。迄今为止，已经鉴定出三种AGE受体，如SR-A（清道夫受体A类）、半乳糖凝集素-3和AGEs（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。使用过表达人半乳糖凝集素-3的CHO细胞进行的体外实验表明，β<125>-AGE-BSA、乙酰化低密度脂蛋白（LDL）和氧化LDL被内吞摄取，随后发生溶酶体降解，表明半乳糖凝集素-3不仅作为AGE受体，而且作为修饰LDL的受体。 关于我们 本研究成功地培育了RAGE转基因小鼠，在心脏、肾脏、肝脏、肺和巨噬细胞中高表达小鼠RAGE。我们在1997年发现A类清道夫受体（SR-A）是AGE受体。CD-36过表达的CHO细胞对AGE-蛋白的内吞摄取和随后的胞内降解，提示原位产生的AGE-蛋白被CD-36识别，这可能参与了糖尿病大血管并发症的发病机制。通过使用SR-BI过表达的CHO细胞（SR-BI-CHO），我们清楚地表明SR-BI也充当AGE受体。此外，SR-BI介导的HDL的胆固醇酯的选择性摄取以及HDL介导的胆固醇从SR-BI-CHO细胞流出被AGE配体有效地竞争，表明AGE配体在HDL介导的体内胆固醇反向转运中起重要作用。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