去乙酰化酶SIRT3在肾小管上皮细胞凋亡及草酸钙肾结石形成中的作用及机制研究

项目名称： 去乙酰化酶SIRT3在肾小管上皮细胞凋亡及草酸钙肾结石形成中的作用及机制研究

项目编号： No.81500531

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 彭泳涵

作者单位： 中国人民解放军第二军医大学

项目金额： 17万元

中文摘要： 肾小管上皮细胞凋亡是肾结石形成的中心环节，线粒体介导的氧化应激起到重要作用，但机制尚不明确。SIRT3 是线粒体内主要的去乙酰化酶，可对多种线粒体蛋白进行去乙酰化，从而维持线粒体结构和功能的稳定。课题组前期研究发现草酸钙结石患者肾组织SIRT3表达较正常肾组织显著降低，线粒体凋亡途径的关键蛋白也发生显著变化。草酸钙肾结晶小鼠肾组织中SIRT3的表达亦显著低于对照组，氧化应激指标明显升高。据此我们推测，草酸钙晶体可通过下调SIRT3的表达削弱其对肾小管上皮细胞的保护作用，诱发氧化应激以及细胞凋亡，从而促进了结石的形成和发展。本研究拟通过体内及体外实验进一步明确草酸钙晶体作用下肾小管上皮细胞SIRT3的变化，及其对线粒体蛋白乙酰化及细胞凋亡的影响；探讨草酸钙晶体下调SIRT3表达的机制、寻找SIRT3靶蛋白及下游信号通路，以阐明SIRT3对肾结石形成的影响,为探索肾结石发病机制提供理论基础。

中文关键词： 肾小管上皮细胞；草酸钙结石；氧化应激损伤；细胞凋亡；去乙酰化酶

英文摘要： The central part of the formation of kidney stones is the apoptosis of renal tubular epithelial cell, which was reported to be associated with oxidative stress mediated by mitochondrion. However, its mechanism has not been clear. SIRT3 is an important deacetyltransferase in the mitochondrion, which can stabilize the structure and function of mitochondrion by deacetylating several important mitochondrial proteins. Our previous study showed that there were significant changes in the main proteins of mitochondrial apoptotic pathway in the renal tissue of the patients with renal calcium oxalate stones, and lower expression level of SIRT3 compared with the control group. Further mice experiments suggested that oxidative stress levels increased in the renal tissue of the nephrolithic mice and SIRT3 expression level was less than control group. Thus we speculated that calcium oxalate crystals decreased the expression of SIRT3 in renal tubular epithelial cells and thus weaken the protective effect of SIRT3, prompting the apoptosis of renal tubular epithelial cells and stone formation. We plan to further clarify the change of SIRT3 under the stimulation of calcium oxalate crystals in vivo and in vitro, and its effect on mitochondrial protein acetylation and apoptosis. Then, to explore the mechanism of stone-dependent downregulation of SIRT3, and find the target proteins and pathways of SIRT3. Thereby, to clarify the impact of SIRT3 on the formation of kidney stones and provide a theoretical basis for exploring the pathogenesis of kidney stones.

英文关键词： renal tubular epithelial cell;calcium oxalate calculus;oxidative stress injury;apoptosis;deacetylase