Thioredoxin-2募集TRIM31泛素化降解NLRP3在糖尿病肾病炎症反应中的作用和机制

NLRP3炎性体激活诱发的炎症级联反应是糖尿病肾病（DN）发生发展的重要原因，但其激活的机制不清楚。我们前期发现硫氧还蛋白Thioredoxin-2（Trx2）在DN患者肾小球内皮细胞表达下调。预实验表明，条件性敲除内皮细胞Trx2（Trx2-ECKO）导致了：NLRP3蛋白上调但不影响其mRNA；显著加重DN炎症反应和肾损伤。相反，高表达Trx2促进NLRP3发生泛素化降解。Co-IP和质谱鉴定表明E3泛素连接酶TRIM31与Trx2相互作用。本课题拟解决“Trx2是否以及如何通过募集TRIM31调节NLRP3介导DN炎症反应”这一关键科学问题，从而验证我们的科学假说，即“DN发生时，肾小球内皮细胞Trx2下调使TRIM31泛素化降解NLRP3的功能减弱，导致NLRP3蛋白上调、炎症小体激活和DN炎性损伤发生”，最终，为确立DN治疗新靶点提供科学依据。

The inflammatory cascade induced by NLRP3 inflammasome activation is an important motivating cause in diabetic nephropathy (DN), but the mechanism of its activation is unclear. We have previously found that thioredoxin-2 (Trx2) was down-regulated in glomerular endothelial cells of patients with DN. Preliminary experiments showed that conditional knock out Trx2 in endothelial cells (Trx2-ECKO) resulted in NLRP3 protein upregulation but not its mRNA, and significantly aggravated inflammatory response and kidney damage of diabetic nephropathy. In contrast, high expression of Trx2 promoted ubiquitination degradation of NLRP3. Co-immunoprecipitation and mass spectrometry identification indicated that E3 ubiquitin ligase TRIM31 interacted with Trx2. Accordingly, we aim to clarify the key scientific question of that whether and how Trx2 recruits TRIM31 to regulate NLRP3 in mediating inflammatory response in diabetic nephropathy. Furthermore, we verify our scientific hypothesis of that diabetic nephropathy occurs, Trx2 down-regulation in glomerular endothelial cells weakens the function of TRIM31 regulating NLRP3 ubiquitin degradation, which leads to the NLRP3 upregulation and activate NLRP3 inflammasome, then promotes inflammatory damage in diabetic nephropathy. Finally, it provides a scientific basis for establishing a new therapeutic target for diabetic nephropathy.