hCINAP在尿毒症毒素相关的心肌损伤中的作用及机制研究

心血管并发症是慢性肾脏病患者死亡的主要原因。尿毒症毒素是导致心血管高炎症病变的重要因素，但具体机制仍不清楚。研究发现hCINAP可以通过降低IKB激酶(IKK)复合物的作用负向调节NF-κB。预实验发现，尿毒症毒素IS处理诱导心肌细胞后hCINAP的表达显著降低；过表达hCINAP 能够抑制IS诱导的NF-κB磷酸化并改善细胞炎症。提示hCINAP可能通过调控NF-κB磷酸化参与了尿毒症毒素引起的心肌损伤。此外，生物信息学分析显示转录因子Oct-1与hCINAP启动子区有结合位点，IS处理也抑制了Oct-1表达，过表达Oct-1则上调了hCINAP。因而推测：IS通过Oct-1下调hCINAP表达，通过激活NF-κB磷酸化及细胞炎症反应，在尿毒症毒素引起的心肌损伤进程中起重要作用。本课题将在动物、细胞和分子水平探讨hCINAP在尿毒症毒素引起的心肌损伤中的作用及机制。

Cardiovascular complications are the leading cause of death in patients with chronic kidney disease. Uremia toxin is an important factor leading to cardiovascular hyperinflammatory diseases, but the specific mechanism is still unclear. HCINAP was found to negatively regulate NF-κB by decreasing the action of the IKB kinase (IKK) complex. Preliminary experiments showed that the expression of HCINAP was significantly decreased after the induction of Uremia toxin IS. Overexpression of HCINAP can inhibit NF-κB phosphorylation and improve cell inflammation.Silencing HCINAP can promote NF-κB phosphorylation and cell inflammation.These results suggest that HCINAP may be involved in uremia toxin-induced myocardial injury by regulating NF-κB phosphorylation. In addition, bioinformatics analysis showed that the transcription factor OCT-1 had binding sites with the promoter region of HCINAP, and IS treatment also decreased the expression of OCT-1, while overexpression of OCT-1 up-regulated HCINAP. Therefore, it was speculated that IS up-regulated the expression of HCINAP through OCT-1, and the latter inhibited cellular inflammatory response by inhibiting the phosphorylation of NF-κB, and played a protective role in the process of myocardial injury induced by uremia toxin. This project will explore the role of HCINAP in the pathogenesis of uremia toxins at animal, cellular and molecular levels.