Role of AGE Receptors in Diabetic Complications

AGE 受体在糖尿病并发症中的作用

• 批准号: 11557081
• 负责人: HORIUCHI Seikoh
• 金额: $ 8.64万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557081/
• 关键词: Diabetic Complications; Maillard Reaction endproduct; AGE; AGE Receptor; Scavenger Receptor; RAGE; Galectin-3; Reverse Cholesterol Transport; ノックアウトマウス

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

蛋白质与葡萄糖长期孵育，通过希夫碱和Amadori产物，形成晚期糖基化终产物（AGE）。近年来对AGE结构及其受体（AGE受体）的研究强调了翻译后AGE修饰在衰老和年龄增强疾病过程中的作用，如糖尿病并发症、动脉粥样硬化和阿尔茨海默病。目前已鉴定出三种AGE受体，如SR-A （A类清除率受体）、半乳糖凝集素-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。在体外实验中，过度表达人半乳糖凝集素-3的CHO细胞显示了^<125>-AGE-BSA，乙酰化低密度脂蛋白（LDL）和氧化LDL的内吞，随后溶酶体降解，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。在RAGE项目中，我们成功开发了RAGE转基因小鼠，在心脏、肾脏、肝脏、肺和巨噬细胞中高度表达小鼠RAGE。他们的生化和形态分析正在进行中。我们早在1997年就发现了a类清道夫受体（SR-A）作为age受体。这一概念在目前被进一步扩展到B类清道夫受体家族，如CD-36和SR-BI。cd -36过表达的CHO细胞表现出对age蛋白的内吞摄取和随后的细胞内降解，表明原位生成的age蛋白被CD36识别，这可能与糖尿病大血管并发症的发病机制有关。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也可作为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SR-BI-CHO细胞中高密度脂蛋白介导的胆固醇外排被age配体有效地竞争，这表明age配体在体内HDL介导的胆固醇逆向转运中发挥了重要作用。少

项目成果

Uesugi,N. et al.: "Glycoxidative modification promotes renal AA amyloid Deposition."Nephrol.Dial.Transplant. 15. 355-365 (2000)

上杉，N.

Shibata N., Hirano.A., Kato, S., Nagai, R., Horiuchi, S., Komori, T., Umahara, T., Asayama, K., Kobayashi, M.: "Advanced glycation endproducts are deposited in neuronal hyaline inclusions : a study on familial amyotrophic lateral sclerosis with superoxide

Shibata N.、Hirano.A.、Kato, S.、Nagai, R.、Horiuchi, S.、Komori, T.、Umahara, T.、Asayama, K.、Kobayashi, M.：“高级糖基化终产物沉积

Kato, S., Horiuchi, S., Nakashima, K., Hirano, A., Shibata, N., Nakano, I., Saito, M., Kato, M., Asayama, K., and Ohama, E.: "Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophic lateral sclerosis with superoxide di

加藤，S.，堀内，S.，中岛，K.，平野，A.，柴田，N.，中野，I.，斋藤，M.，加藤，M.，浅山，K.，和大滨，E。

Kaji Y, Usui T, Oshika T, Matsubara M, Yamashita H, Araie M, Murata T, Ishibashi T, Nagai R, Horiuchi S, Amano S: "Advanced glycation end products in diabetic corneas."Invest.Ophthalmol.Vis.Sci.. 41. 362-368 (2000)

Kaji Y、Usui T、Oshika T、Matsubara M、Yamashita H、Araie M、Murata T、Ishibashi T、Nagai R、Horiuchi S、Amano S：“糖尿病角膜的高级糖基化终产物。”Invest.Ophthalmol.Vis.Sci

Uesugi, N.Sakata, N., Nagai, R., Johno, T., Horiuchi, S., Takebayashi, S.: "Glycoxidative modification promotes renal AA amyloid Deposition"Nephrol.Dial.Transplant.. 15. 355-365 (2000)

Uesugi, N.Sakata, N.、Nagai, R.、Johno, T.、Horiuchi, S.、Takebayashi, S.：“糖氧化修饰促进肾 AA 淀粉样蛋白沉积”Nephrol.Dial.Transplant.. 15. 355-365