尿毒症毒素硫酸盐对甲酚（PCS）促进心功能不全发生机制研究

本研究探讨尿毒症毒素硫酸盐对甲酚（PCS）对慢性肾病时心功能不全的影响。前期研究中，我们发现慢性肾病患者血清PCS水平与舒张性心衰相关。对5/6肾切除小鼠进行PCS灌胃，3月后心肌组织较对照小鼠舒张功能减退，炎症、凋亡和纤维化增加。mRNA芯片发现并证实PCS干预后心肌组织较对照组织中缓激肽相关肽酶（KLK）6和肽基精氨酸脱亚胺酶（PADI）6表达显著升高。PCS还诱导终末糖化产物形成。KLK6促进心肌细胞炎症、纤维化和重构；PADI6诱导心肌细胞炎症和凋亡。此二者基因介导了PCS和PCS修饰蛋白的病理效应，结合文献提示这是PCS致心功能不全新机制。后续研究在5/6肾切除野生型和RAGE-KO小鼠、体外心肌细胞，给予PCS和PCS修饰蛋白干预，利用腺病毒siRNA下调KLK6和PADI6，添加氧化应激抑制剂等手段，阐明PCS经KLK6和PADI6介导促进肾功能不全小鼠舒张性心衰发生机制。

The present study aimed to investigate the impact of p-cresyl sulfate on cardiac dysfunction in chronic renal insufficiency. We have shown that serum levels of p-cresyl sulfate is associated with diastolic heart failure in patients with chronic kidney diseases. In experiments, we established renal insufficiency mouse models with 5/6 nephrectomy and PCS was given by oral gavage every day. After 3 months, echocardiography examination showed that PCS administration significantly impaired diastolic function in nephrectomized mice, with augmentation of inflammation, apoptosis, and fibrosis in myocardial tissues. mRNA microarray analysis was performed to compare myocardial tissue from mice with PCS administration with that from controls, which demonstrated that Kallikrein related-peptidase（KLK）6 and peptidyl arginine deiminase（PADI）6 were significantly elevated in the former tissue. Moreover, PCS promoted the formation of advanced glycation end products (AGEs). Our experiment showed KLK6 increased inflammatory reaction, fibrosis and remodeling in myocardial cells H9C2, while PADI6 induced inflammatory and apoptosis. KLK6 and PADI6 mediated induction of pathology by PCS and glycated bovine serum albumin modified by PCS. In our future experiments, we will use wide-type and RAGE-KO mice with 5/6 nephrectomy to investigate the mechanisms of KLK-6- or PADI6-mediated PCS effects regarding diastolic dysfunction, with adenoviral siRNA-KLK6 or siRNA-PADI6 and ROS inhibitor APO.