线粒体调节NLRP3炎症小体在DKD小管和间质损伤中的作用与机制及Epac1在其中的干预研究

Diabetic kidney disease (DKD) is one of the leading causes of ESRD. Tubulo-interstitial injury has proved to be an important pathological mechanism of DKD. The role of micro-inflammatory cytokines，especially IL-1β、IL-18 in the pathogenesis of tubulo-interstitial injury has received increasing attention. However, in DKD, the underlying mechanism remains largely elusive. Recent evidence shown that mitochondria modulated NLRP3/IL-1β biological axis which has an essential role in the activation of inflammatory cytokines, including IL-1β、IL-18、TNF-α、ICAM、INF-γ、TGF-βand FN. Epac1, as an important downstream molecule of cAMP, is mainly expressed in tubular epithelial cells and involved in regulating the production of reactive oxygen species (ROS). In this proposal, we will perform in vitro and in vivo studies to dissect the role of mitochondrial ROS modulated NLRP3/IL-1β axis in tubulo-interstitial injury in DKD and the underlying mechanism, to understand how mitochondrial ROS activates NLRP3 inflammasome, and to verify whether Epac1 exert its actions in tubulo-interstitial compartment via mitochondrial ROS/NLRP3/IL-1β biological axis. The goal of this proposal is to dissect the role and underlying mechanisms of inflammation in tubulo-interstitial damage in order to provide scientific and experimental direction for the treatment of DKD in future.

糖尿病肾病（DKD）是常见的继发性肾脏病，也是引起ESRD的主要病因。肾小管及间质慢性微炎症损伤在DKD发病中的作用日益受到重视。近期研究证明促炎症细胞因子IL-1β、IL-18异常表达在DKD肾组织慢性微炎症的发生中起关键作用，但其成熟激活的分子调控机制尚不清楚。已知线粒体在调节NLRP3炎症小体激活、促进IL-1β、IL-18剪切成熟中起"调控器"作用，但是否介导DKD小管及间质微炎症损伤尚不清楚。我们前期发现：cAMP下游的效应分子Epac1主要表达在小管上皮细胞，能调节小管细胞病理生理功能及线粒体ROS产生等。本项目采用动物及细胞分子生物学技术，体内外研究线粒体调节NLRP3炎症小体/IL-1β分泌轴在DKD小管及间质损伤中的作用与机制，探讨Epac1是否通过此轴干预DKD进展及其相关机理。旨在揭示DKD小管及间质微炎症损伤的分子发病机制，为今后DKD诊疗提供新的干预靶点。

糖尿病肾病是引起ESRD的主要病因，肾小管及间质微炎症损伤在DKD发病中起重要作用，但机制尚不十分清楚。本项目主要围绕以下7个问题展开研究：①线粒体调节的NLRP3炎症小体/IL-1β分泌轴在DKD小管及间质损伤中的作用机制；②Epac1 调节线粒体ROS/NLRP3/IL-1β分泌轴的作用与机制，；③异位脂肪沉积在糖尿病肾病肾损伤的可能相关机制；④ MitoQ改善糖尿病肾病小管损伤的可能分子机制；⑤普罗布考是否通过抑制p66Shc表达改善糖尿病肾病的氧化损伤；⑥临床研究：红细胞分布宽度以及p66Shc是否可作为糖尿病肾病患者治疗和预后的标志物；⑦综合阐述：线粒体功能紊乱在糖尿病肾病发病机制中的重要作用以及对非白蛋白尿性糖尿病肾病的新认识等。总之，本项目证明了线粒体调节NLRP3炎症小体/IL-1β分泌轴在糖尿病肾病小管及间质损伤中的作用机制。在本项目的资助下，在Redox Biology ，Scientific Report等杂志共发表SCI论文14篇，培养毕业学生7名，参与国际会议2次。