TXNIP在高糖诱导小鼠肾小球系膜细胞自噬中的作用及 分子机制-病理学与病理生理学专业论文.docxVIP

万方数据 万方数据 目 录 中文摘要 ················································································1 英文摘要 ················································································4 英文缩写 ················································································8 研究论文 TXNIP 在高糖诱导小鼠肾小球系膜细胞自噬中的作用及分子 机制 前言 ················································································9 材料与方法 ····································································· 11 结果 ·············································································· 21 附图 ·············································································· 23 讨论 ·············································································· 33 结论 ·············································································· 35 参考文献 ········································································ 36 综述 自噬与糖尿病肾病关系的研究进展 ···································· 42 致谢 ···················································································· 53 个人简历 ·············································································· 54 中 中 文 摘 要 PAGE 1万方数据 PAGE 1 万方数据 TXNIP 在高糖诱导小鼠肾小球系膜细胞自噬中的作用 及分子机制 摘 要 目的：糖尿病肾病（Diabetic nephropathy,DN）是糖尿病最常见的并 发症之一，糖尿病患者一旦出现明显蛋白尿则病情通常难以逆转，往往发 展至终末期肾功能衰竭，是导致糖尿病患者死亡的主要原因之一。 近年来的研究发现，细胞自噬（Autophagy）在 DN 中扮演着重要的 角色。自噬是细胞内一个基本过程，它将细胞内成分运输到溶酶体降解， 维持着体内平衡和细胞完整性。正常情况下，细胞自噬功能处于基础水平， 以维持细胞正常的生理功能。越来越多的研究表明，细胞自噬受损与糖尿 病肾病之间密切相关，并参与了糖尿病肾病的发生与发展。在 STZ 诱导 的早期糖尿病小鼠肾小管上皮细胞中，自噬标志物 LC3-II 和自噬溶酶体 降解产物 P62 表达增多提示自噬活性可能减弱。 硫氧还蛋白相互作用蛋白（Thioredoxin interacting protein,TXNIP）在 细胞内普遍存在，高糖能够诱导 TXNIP 过表达，导致细胞发生氧化应激 反应，引起细胞损伤和细胞外基质蛋白沉积，促进细胞凋亡。我们先前已 有 研 究 表 明 高 糖 诱 导 的 系 膜 细 胞 TXNIP 表 达 明 显 上 调 ， 活 性 氧 （Reactive oxygen species,ROS）产生增多，系膜细胞出现凋亡与表型转化。 目前，有研究结果显示，糖尿病肾病患者的肾小管上皮细胞自噬活性 减弱，自噬体累积过多，自噬标志蛋白 LC3-II 和溶酶体降解标记物 P62 表达增高；在肾小管上皮 HK-2 细胞中，敲低 TXNIP 后自噬活性明显增 强，提示 TXNIP 与糖尿病肾小管细胞自噬损伤有关。但是，TXNIP 在高 糖诱导的肾小球系膜细胞自噬中的作用还未见报道。因此，本实验通过体 外培养的小鼠系膜细胞（Mouse mesangial ce