Complement Induces Podocyte Pyroptosis in Membranous Nephropathy by Mediating Mitochondrial Dysfunction

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Mar 30

PMID 35351877

Authors

Hui Wang

Daoyuan Lv

Song Jiang

Qing Hou

Lei Zhang

Shen Li

Xiaodong Zhu

Xiaodong Xu

Jianqiang Wen

Caihong Zeng

Mingchao Zhang

Fan Yang

Zhaohong Chen

Chunxia Zheng

Jing Li

Ke Zen

Zhihong Liu

Limin Li

Affiliations

Soon will be listed here.

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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