2. Academic Validation
  3. Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure

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

  • Sci China Life Sci. 2023 Oct 7. doi: 10.1007/s11427-022-2365-1.
Hongxia Ruan # 1,  Xuejuan Li # 2 3,  Lina Zhou # 4,  Zihan Zheng 5,  Rulin Hua 1,  Xu Wang 6,  Yuan Wang 1,  Yujie Fan 1,  Shuwen Guo 1,  Lihua Wang 7,  Shafiq Ur Rahman 1,  Ziwei Wang 1,  Yuyuan Wei 1,  Shuangyan Yu 7,  Rongzhi Zhang 7,  Qian Cheng 7,  Jie Sheng 7,  Xue Li 7,  Xiaoyan Liu 7,  Ruqiang Yuan 1,  Xiaoyan Zhang 8,  Lihong Chen 1 8,  Guowang Xu 4,  Youfei Guan 1 8,  Jing Nie 9,  Hongqiang Qin 10,  Feng Zheng 11 12 13
Affiliations

Affiliations

  • 1 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
  • 2 Department of Nephrology, Second Hospital, Dalian Medical University, Dalian, 116023, China. clairesnow@126.com.
  • 3 Wuhu Hospital and Health Science Center, East China Normal University, Shanghai, 200241, China. clairesnow@126.com.
  • 4 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
  • 5 Chongqing International Institute for Immunology, Chongqing, 401320, China.
  • 6 Department of Nephrology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518101, China.
  • 7 Department of Nephrology, Second Hospital, Dalian Medical University, Dalian, 116023, China.
  • 8 Wuhu Hospital and Health Science Center, East China Normal University, Shanghai, 200241, China.
  • 9 Peking University First Hospital, Peking University, Beijing, 100034, China.
  • 10 CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China. qinhq@dicp.ac.cn.
  • 11 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China. zhengfeng@dmu.edu.cn.
  • 12 Department of Nephrology, Second Hospital, Dalian Medical University, Dalian, 116023, China. zhengfeng@dmu.edu.cn.
  • 13 Wuhu Hospital and Health Science Center, East China Normal University, Shanghai, 200241, China. zhengfeng@dmu.edu.cn.
  • # Contributed equally.
PMID: 37815699 DOI: 10.1007/s11427-022-2365-1
Abstract

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.

Keywords

GSDME; mTOR; melatonin; mitochondria; peritoneal fibrosis; pyroptosis.

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