新型Nrf2激活剂DDO-1039对糖尿病肾病疗效及其调控足细胞稳态机制研究

糖尿病肾病（DKD）是终末期肾脏病主因，足细胞损伤是DKD预后关键因素，急需创新疗法。氧化应激和炎症是DKD肾组织和足细胞损伤关键因素，Nrf2是抗氧化，维持机体稳态的重要转录因子，其激动剂具有显著肾脏保护作用，是创新药物重要靶点。DDO-1039是自主优化设计的Nrf2靶向激活剂，前期研究显示其显著改善DKD小鼠肾脏和足细胞病变，降低足细胞氧化应激、炎症和凋亡。重要的是，Nrf2活化改善受损足细胞骨架结构，且Nrf2调控足细胞重要功能蛋白SRGAP2a和Tyro3。本研究拟在前期研究基础上，验证DDO-1039对DKD疗效，分析其对足细胞氧化应激、骨架和凋亡等功能和相关分子影响；应用单细胞测序和CUT&Tag等探寻Nrf2对足细胞特异性调控通路和靶点，重点关注与骨架和凋亡调节相关靶点。初步解析Nrf2调控足细胞稳态的分子基础；本项目对于探索DKD致病机理、创新药物研发应用有重要意义。

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and there is an urgent need for innovative therapies. Oxidative stress and inflammation are the key elements associated with DKD. Transcription factor Nrf2 plays a central role in the defense against oxidative stress. Strategies aimed at restoring Nrf2 activity could potentially retard DKD progression. Keap1-Nrf2 protein-protein interaction (PPI) inhibitor DDO-1039 is an optimized Nrf2 activator. Previous studies have shown that DDO-1039 significantly improved the kidney pathology and podocyte injuries in DKD mice, as well as reduced podocyte oxidative stress, inflammation and apoptosis. Importantly, Nrf2 activation stabilized podocyte cytoskeleton. Further studies showed that Nrf2 transcriptionally regulated SRGAP2a and Tyro3, which are podocyte protective factors. In this program, we evaluate efficacy and safety of DDO-1039 on diabetic nephropathy mice, analyze its effects on oxidative stress, cytoskeleton and apoptosis in podocyte. Exploring Nrf2 on podocyte specific regulatory pathways and targets with CUT&Tag, focusing on genes and pathways related with cytoskeleton and apoptosis. This study is of great significance for exploring the molecular mechanism of DKD and developing DKD therapeutic drug with self-owned intellectual property rights.