TRAIL诱骗受体DcR2介导糖尿病肾病衰老肾小管上皮细胞凋亡逃逸的作用及机制

Stress-induced senescence plays a fundamental role in the pathogenesis of diabetic nephropathy (DN), and its harmful effects could be amplified and prolonged due to the escape of senescent cell from apoptosis. Nevertheless its mechanism is unknown. It has been proven that TNF-related apoptosis-inducing ligand (TRAIL) is one of the main inflammatory cytokines accelerating the progression of DN through inducing cellular apoptosis.Howere, we unexpectly found that DcR2,the TRAIL antagonist receptor, was highly expressed on the senescent renal tubular cells.We supposed that this paradoxical phenomenon might be linked to the escape of senescent tubular cell from apoptosis. This project intends to verify the relationships between TRAIL receptors including DcR2 and celluar senescence or apotosis invivo and in vitro, and whether inhibing DcR2 could enhance the senescent cell apoptosis. Then, to explore whether PI3K/Akt/FoxO1is the key signal pathway for DcR2-mediated apoptosis escape of senescent renal tubular cells. finaly , to observe whether alteration of the key molecules of this pathway could influnce apoptosis escape of senescence cells in DN. By this project, a novel mechanism could how senescent tubular cells escaped from apoptosis, which was fundamental for the therapy based on clearance of senscent cells in DN.

细胞应激衰老是糖尿病肾病（DN）的重要病理基础，衰老细胞凋亡逃逸是其损害放大和迁延的中心环节，但机制不明。TNF相关凋亡诱导配体（TRAIL）是加速DN进展最主要致凋亡炎症因子，但我们意外地发现DN患者衰老肾小管细胞高表达其拮抗型受体DcR2，推测DcR2可能与衰老肾小管细胞凋亡逃逸有关。为此，本项目拟进一步求证DN小鼠和培养肾小管细胞TRAIL及其激动型受体和DcR2表达变化与细胞衰老和凋亡之间的关系；拮抗DcR2是否可以促进DN衰老肾小管细胞凋亡；探明DcR2介导衰老肾小管细胞凋亡逃逸的关键信号通路是否为PI3K/Akt/FoxO1; 改变信号通路关键分子活性对DN衰老肾小管细胞凋亡逃逸的影响。本项目提出并证明DN进展中衰老细胞凋亡逃逸新机制，为以清除衰老细胞治疗DN的新策略奠定理论基础.

细胞应激衰老是应激引发与增龄无关的细胞周期停滞，通过释放衰老相关分泌表型（SASP）和呈现凋亡逃逸特性，导致组织器官不可逆损伤、功能丢失和修复障碍。肾小管细胞应激衰老是糖尿病肾病（DN）不可逆进展的重要机制，是导致肾组织炎症与纤维化、肾功能损害最主要的原因之一。我们研究发现DN肾组织和尿液中DcR2水平升高，与肾组织损伤及肾功能损害密切关联。同时发现DcR2高表达于衰老肾小管细胞，后续通过体内外调控DcR2表达变化证明了DcR2介导DN肾小管细胞衰老表型。为了进一步明确DcR2在细胞衰老过程中的相互作用蛋白，我们在组织和细胞层面采用了定量蛋白组学分析，结果发现DcR2与抗氧化酶PRDX1相互作用，并且DcR2通过调节PRDX1磷酸化抑制其抗氧化酶活性进而发挥作用。基于DcR2在DN衰老肾小管细胞中的作用及机制，我们创建了尿DcR2检测方法，评估了尿DcR2对DN肾组织损伤严重程度的诊断价值。同时构建了基于DcR2的衰老细胞分选方法，为衰老细胞的作用及机制研究奠定了基础。本项目从新的视角解析衰老肾小管细胞在DN进展中的作用及机制，进而为靶向清除衰老细胞防治DN的新策略提供了新的理论基础。.现已发表4篇SCI文章，6篇中文论文。研究成果在2016年欧洲肾脏病与透析－肾移植年会和2018年亚太地区国际肾脏病年会上进行大会报告，被选为2016年中华医学会肾脏病年会的优秀壁报。申请了两项发明专利。资助培养5名硕士研究生。