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

查看全文 作　　者：Hongxia [1]Ruan;Xuejuan [2,6]Li;Lina [3]Zhou;Zihan [4]Zheng;Rulin [1]Hua;Xu [5]Wang;Yuan [1]Wang;Yujie [1]Fan;Shuwen [1]Guo;Lihua [2]Wang;Shafiq ur [1]Rahman;Ziwei [1]Wang;Yuyuan [1]Wei;Shuangyan [2]Yu;Rongzhi [2]Zhang;Qian [2]Cheng;Jie [2]Sheng;Xue [2]Li;Xiaoyan [2]Liu;Ruqiang [1]Yuan;Xiaoyan [6]Zhang;Lihong [1,6]Chen;Guowang [3]Xu;Youfei [1,6]Guan;Jing [7]Nie;Hongqiang [3]Qin;Feng [1,2,6]Zheng

机构地区：[1]Advanced Institute for Medical Sciences,Dalian Medical University,Dalian 116044,China;[2]Department of Nephrology,Second Hospital,Dalian Medical University,Dalian 116023,China;[3]CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China;[4]Chongqing International Institute for Immunology,Chongqing 401320,China;[5]Department of Nephrology,Shenzhen Hospital,Southern Medical University,Shenzhen 518101,China;[6]Wuhu Hospital and Health Science Center,East China Normal University,Shanghai 200241,China;[7]Peking University First Hospital,Peking University,Beijing 100034,China

出　　处：《Science China(Life Sciences)》索引2024年第67卷第2期,共19页

基　　金：supported by the National Key Research and Development Program of China(2020YFC2005002);the National Natural Science Foundation of China(81970642,81370460,81700580,81670668,22222409);Key research and development grant from The Department of Science and Technology,Liaoning Province;Innovative Leading Researcher grant from the Department of Science and Technology,Dalian,and Key Laboratory of Immune,Genetic and Metabolic Kidney Diseases,Dalian,and Youth Innovation Promotion Association of CAS(2018212)。 摘　　要：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 m TOR 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. 关键词：MELATONIN MITOCHONDRIA PYROPTOSIS GSDME peritoneal fibrosis MTOR

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

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