基于DcR2靶向清除衰老肾小管上皮细胞防治糖尿病肾病的作用及机制

Stress-induced senescence is an arrest of cell cycle which is caused by stress and it isn’t related to age. Senescent cell can result in irreversible damage, dysfunction and repair obstacles in organs via releasing senescence-associated secretory phenotype (SASP) and inhibiting cell proliferation and regeneration. Renal tubular cell senescence is a critical mechanism in the irreversible progression of diabetic nephropathy (DN), and it is one of main reasons for leading to renal inflammation and fibrosis and renal function damage. Our previous studies proved that DcR2 was a specific marker of senescent renal tubular cells, and it mediated apoptotic resistance. Renal DcR2 was associated with renal tissue injury and function damage. This project aims to investigate the role of inhibiting renal inflammation and fibrosis and promoting tissue repair by targeted clearance of senescent renal tubular cells basing on DcR2 with inducible DcR2 gene knockout mice. And verify TRAIL-DR5 signaling promoting apoptosis of senescent renal tubular cells. We firstly investigate the role and mechanism of targeted clearance of senescent renal tubular cells basing on DcR2 in the progression of DN. The project will lay a theoretical foundation for the new strategy in prevention and treatment of DN.

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）和抑制细胞增殖与再生，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。我们前期研究证实衰老肾小管细胞特异性标志DcR2介导了衰老细胞凋亡抵抗，与DN肾组织损伤及肾功能损害密切相关。本项目拟用诱导性DcR2基因敲除小鼠构建DN模型，探索DcR2靶向清除衰老肾小管细胞对肾组织炎症、纤维化的抑制和促进组织细胞修复的作用，验证TRAIL-DR5信号促进了衰老肾小管细胞凋亡从而清除衰老细胞。本项目首次提出并证明基于DcR2靶向清除衰老肾小管细胞在防治DN进展中的作用及机制，为未来防治DN进展的新策略奠定了理论基础。

肾小管细胞应激衰老是糖尿病肾病（DN）进展的重要病理基础，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DcR2表达水平升高，与肾组织病理损伤评分及肾功能损害指标密切关联。同时发现DcR2特异性高表达于衰老肾小管细胞，与纤维化指标共定位。进一步体内外调控DcR2表达变化，明确了DcR2可通过介导DN肾小管细胞衰老表型加速肾间质纤维化。后续我们在组织和细胞层面采用了定量蛋白组学及生物信息学，分析了DcR2在细胞衰老过程中的关键相互作用蛋白。通过体内外实验，并结合免疫荧光共染、CO-IP等多种实验技术证明了DcR2与抗氧化酶PRDX1相互作用。同时调控DcR2和PRDX1可介导肾小管细胞衰老表型，机制研究证明了DcR2是通过调节PRDX1磷酸化抑制其抗氧化酶活性进而介导肾小管细胞衰老。本项目从新的视角解析肾小管细胞衰老在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5篇SCI文章，1篇中文论文。相关研究成果在2019年美国肾脏病年会（ASN）和2020年欧洲肾脏病与透析－肾移植年会（EDTA）进行大会报告，被获2019年欧洲肾脏病年会“Outstanding scientific presentation”和“Travel grants”。资助培养3名硕士研究生.