NEK7介导的NLRP3炎症小体活化在尿毒症毒素引起的血管内皮损伤中的作用

终末期肾病（ESRD）患者的心血管事件显著增加，尿毒症毒素被认为是引起血管病变的重要因素，但具体机制尚不清。预实验显示，尿毒症毒素硫酸吲哚酚(IS)可以诱导血管内皮细胞（EC）凋亡，降低eNOS磷酸化，并上调NEK7和NLRP3的表达，而抑制NEK7减轻了IS对EC的损伤作用。生物信息学预测发现，NEK7启动子区域存在转录因子Ash1的结合位点，且IS可上调Ash1的表达，敲低Ash1可下调NEK7，提示Ash1是NEK7的上游调控因子。近期研究还显示NEK7可能是NLRP3炎症小体的新组分。由此推测，NEK7/NLRP3炎症小体通路可能在Ash1的调控下介导了IS引起的血管内皮损伤。本研究将在动物、细胞及分子层面探讨NEK7介导的NLRP3炎症小体活化在尿毒症毒素引起EC损伤中的作用，为临床防治ESRD的心血管病变提供新视点。

The cardiovascular events remarkably increased in the patients with end stage renal diseases. The detrimental effect of uremic toxins, especially protein-bound uremic toxins, has been thought as one of the factors contributing to the vascular injury with uncertain mechanisms. Our preliminary data showed that indoxyl sulfate (IS) one of the common uremic toxins could induce mouse endothelial cell apoptosis and decreased phosphorylated eNOS. Meantime,Ash1,NEK7（a newly defined component of NLRP3 inflammasome）and NLRP3 were upregulated following IS chanllenge. Moreover, bioinformatics analysis indicated nine biding sites of transcriptional factor Ash1 in the promoter region of NEK7. Also, IS treatment similarly inhanced the expressions of Ash1 and NEK7, and scilencing of Ash1 reduced NEK7 expression, suggesting that Ash1 could be a upstream regulator of NEK7. In consideration of the proinflammatory property of NLRP3 inflammasome in many disease conditions, these findings may suggest that Ash1 regulated NEK7/NLRP3 activation might participate in IS-induced vascular endothelial dysfunction and contribute to CKD-related high risk of cardiovascular events. In the present proposal, employing the models of animal,cell and molecule, we will fully investigate the role of Ash1 regulated NEK7/NLRP3 activation in IS-induced vascular endothelial injury and dysfunction. The findings from current project will not only increase our understanding on the pathogenic mechanisms of uremic toxin-related vascular injury but also bring the new insights into the treatment of CKD-related cardiovascular diseases.