再探肾脏损伤的端粒缩短触发炎症细胞捕获机制

Kidney injury can ultimately develop into uremia in an irreversible way, the diversified pathogenesis of which is still under research. Previous studies revealed that a group of specific proteins secreted by telomere defect aging cells can predict the genesis and development of consenescence and chronic diseases, among which LL37 was found associated with kidney diseases. LL37 was secreted by telomere defect cells and interact with inflammatory cells. It could influence on small vessel vasculitis (SVV) related kidney injury in a specific way but rarely had influence on IgA nephropathy. Based on the above, it can be inferred that telomere dysfunction may play a crucial role in SVV induced kidney injury. Therefore, in this study, we assume that telomere shortening may promote neutrophil ageing and SVV related kidney injury. Firstly, length of telomere and expression level of LL37 in SVV patients need to be measured and analyzed，and the relationship of neutrophil ageing and disease progression need to be demonstrated. Then telomere defect (mTERC-/-) mice are used in vivo and in vitro experiments to study the influence of telomere defect on neutrophil ageing and cell function. Also, the MPO-induced SVV related kidney injury model in mTERC-/- mice is applied to investigate the mechanism that telomere dysfunction induces LL37 and promotes neutrophil ageing and cell function, so as to provide new evidence for SVV related kidney injury and ageing.

肾脏损伤因其特殊的不可逆进展而导致尿毒症，其多元的发病机制至今未明。申请人前期研究发现由端粒缺陷诱发细胞衰老分泌的一组特异性蛋白质，能预示衰老和慢性疾病的发生发展。从中锁定了LL37与肾脏疾病特异性相关，并发现端粒缺陷诱发分泌LL37造成中性粒细胞衰老和捕获功能异常增多，并特异性的影响小血管炎肾脏损伤。由此提出“端粒缩短触发中性粒细胞衰老造成小血管炎性肾损伤”的假说。本项目将从临床小血管炎患者体内证实中性粒细胞衰老伴有端粒长度的缩短、LL37表达增加，并由此造成中性粒细胞捕获功能异常增多与肾脏损伤疾病进展的关系；然后应用端粒缺陷小鼠（mTERC-/-）在体内、外研究端粒缩短功能异常对中性粒细胞衰老和捕获功能的影响；并应用MPO在mTERC-/-小鼠诱发小血管炎肾损伤模型，阐明端粒缩短触发中性粒细胞衰老造成小血管炎性肾损伤的分子机制。

肾脏损伤因其特殊的不可逆进展而导致尿毒症，其多元的发病机制至今未明。课题组前期研究发现由端粒缺陷诱发细胞衰老分泌的一组特异性蛋白质，能预示衰老和慢性疾病的发生发展。从中锁定了LL37与肾脏疾病特异性相关，并发现端粒缺陷诱发分泌LL37造成中性粒细胞衰老和捕获功能异常增多，并特异性的影响小血管炎肾脏损伤。由此提出“端粒缩短触发中性粒细胞衰老造成小血管炎性肾损伤”的假说。在本项目研究中从临床小血管炎患者体内证实中性粒细胞衰老伴有端粒长度的缩短、LL37表达增加，并由此造成中性粒细胞捕获功能异常增多与肾脏损伤疾病进展之间存在密切相关关系；然后应用端粒缺陷小鼠（mTERC-/-）在体内、外研究端粒缩短功能异常对中性粒细胞衰老和捕获功能的影响；并应用MPO在mTERC-/-小鼠诱发小血管炎肾损伤模型，阐明端粒缩短触发中性粒细胞衰老造成小血管炎性肾损伤的分子机制。研究成果包括发表6篇SCI论文，其中1篇为一区TOP杂志论文，同时申请了发明专利尚在审核过程中，培养了3名博士研究生，课题负责人获得了中华医学会肾脏病学分会杰出青年研究者。