首页|Melatonin decreases GSDME mediated mesothelial cell pyrop-tosis and prevents peritoneal fibrosis and ultrafiltration failure

Melatonin decreases GSDME mediated mesothelial cell pyrop-tosis and prevents peritoneal fibrosis and ultrafiltration failure

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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 mi-tochondrial integrity in mesothelial cells,meanwhile activating mTOR signaling through an increase in the glycolysis product dihydrox-yacetone 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.

melatoninmitochondriapyroptosisGSDMEperitoneal fibrosismTOR

Hongxia Ruan、Xuejuan Li、Lina Zhou、Zihan Zheng、Rulin Hua、Xu Wang、Yuan Wang、Yujie Fan、Shuwen Guo、Lihua Wang、Shafiq ur Rahman、Ziwei Wang、Yuyuan Wei、Shuangyan Yu、Rongzhi Zhang、Qian Cheng、Jie Sheng、Xue Li、Xiaoyan Liu、Ruqiang Yuan、Xiaoyan Zhang、Lihong Chen、Guowang Xu、Youfei Guan、Jing Nie、Hongqiang Qin、Feng Zheng

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Advanced Institute for Medical Sciences,Dalian Medical University,Dalian 116044,China

Department of Nephrology,Second Hospital,Dalian Medical University,Dalian 116023,China

Wuhu Hospital and Health Science Center,East China Normal University,Shanghai 200241,China

CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China

Chongqing International Institute for Immunology,Chongqing 401320,China

Department of Nephrology,Shenzhen Hospital,Southern Medical University,Shenzhen 518101,China

Peking University First Hospital,Peking University,Beijing 100034,China

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National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaKey research and development grant from The Department of Science and TechnologyLiaoning Province,Innovative Leading Researcher grant from the Department of Science and TechnologyDalian,and Key Laboratory of Immune,Genetic and Metabolic Kidney Diseases,DalianYouth Innovation Promotion Association of CAS

2020YFC200500281970642813704608170058081670668222224092018212

2024

10.1007/s11427-022-2365-1

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(2)
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