1. Academic Validation
  2. Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction

Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction

  • Cell Death Dis. 2022 Mar 29;13(3):281. doi: 10.1038/s41419-022-04737-5.
Hui Wang 1 Daoyuan Lv 1 Song Jiang 1 Qing Hou 1 Lei Zhang 2 Shen Li 1 Xiaodong Zhu 1 Xiaodong Xu 1 Jianqiang Wen 1 Caihong Zeng 1 Mingchao Zhang 1 Fan Yang 1 Zhaohong Chen 1 Chunxia Zheng 1 Jing Li 2 Ke Zen 2 3 Zhihong Liu 4 Limin Li 5
Affiliations

Affiliations

  • 1 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, Jiangsu, China.
  • 3 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 4 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China. liuzhihong@nju.edu.cn.
  • 5 State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China. liminli@cpu.edu.cn.
Abstract

Podocyte damage mediated by in situ complement activation in the glomeruli is a key factor in the pathogenesis of membranous nephropathy (MN), but the molecular mechanism has not been fully elucidated. Pyroptosis is a special type of programmed cell death, mediate inflammatory response and induce tissue injury. However, it is not clear whether Pyroptosis is involved in the development and progression of MN. Here, we report that Pyroptosis plays an important role in promoting podocyte injury in MN. We first observed the occurrence of Pyroptosis in the kidneys of MN patients and validated that complement stimulation triggered Pyroptosis in podocytes and that inhibiting Pyroptosis reversed complement-induced podocyte damage in vitro. In addition, stimulation of complement caused mitochondrial depolarization and Reactive Oxygen Species (ROS) production in podocytes, and inhibition of ROS reversed complement-induced Pyroptosis in podocytes. Interestingly, inhibition of Pyroptosis in turn partially alleviated these effects. Furthermore, we also found the involvement of Pyroptosis in the kidneys of passive Heymann nephritis (PHN) rats, and inhibitors of pyroptosis-related molecules relieved PHN-induced kidney damage in vivo. Our findings demonstrate that Pyroptosis plays a critical role in complement-induced podocyte damage in MN and mitochondrial dysfunction is an important mechanism underlying this process. It provides new insight that Pyroptosis may serve as a novel therapeutic target for MN treatment in future studies.

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