Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure

• Published in: Science China. Life sciences Vol. 67; no. 2; pp. 360 - 378
• Main Authors: Ruan, Hongxia, Li, Xuejuan, Zhou, Lina, Zheng, Zihan, Hua, Rulin, Wang, Xu, Wang, Yuan, Fan, Yujie, Guo, Shuwen, Wang, Lihua, ur Rahman, Shafiq, Wang, Ziwei, Wei, Yuyuan, Yu, Shuangyan, Zhang, Rongzhi, Cheng, Qian, Sheng, Jie, Li, Xue, Liu, Xiaoyan, Yuan, Ruqiang, Zhang, Xiaoyan, Chen, Lihong, Xu, Guowang, Guan, Youfei, Nie, Jing, Qin, Hongqiang, Zheng, Feng
• Format: Journal Article
• Language: English
• Published: Beijing Science China Press 01-02-2024; Springer Nature B.V
• Subjects: Angiogenesis; Animal models; Animals; Biomedical and Life Sciences; Capillaries; Caspase-3; Cell activation; Dihydroxyacetone phosphate; Epithelial Cells; Fibrosis; Free radicals; Glucose; Glucose - pharmacology; Glycolysis; Hemodialysis; Humans; Inflammation; Life Sciences; Macrophages; Melatonin; Melatonin - pharmacology; Melatonin - therapeutic use; Mesothelium; Mice; Peritoneal dialysis; Peritoneal Fibrosis - etiology; Peritoneal Fibrosis - pathology; Peritoneal Fibrosis - prevention & control; Peritoneum; Pyroptosis; Research Paper; TOR protein; Ultrafiltration; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; peritoneal fibrosis; mTOR; pyroptosis; melatonin; mitochondria; GSDME
• ISSN: 1674-7305; 1869-1889
• DOI: 10.1007/s11427-022-2365-1

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure. Mesothelial cell loss is an initiating event for peritoneal fibrosis. We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E, driving downstream inflammatory responses, including the activation of macrophages. Moreover, pyroptosis is associated with elevated vascular endothelial growth factor A and C, two key factors in vascular angiogenesis and lymphatic vessel formation. GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure. Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action, and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy. Mechanistically, melatonin treatment maintains mitochondrial integrity in mesothelial cells, meanwhile activating mTOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate. These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress. Thus, Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.