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Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction.

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.

SUBMITTER: Wang H

PROVIDER: S-EPMC8964685 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction.

Wang Hui H Lv Daoyuan D Jiang Song S Hou Qing Q Zhang Lei L Li Shen S Zhu Xiaodong X Xu Xiaodong X Wen Jianqiang J Zeng Caihong C Zhang Mingchao M Yang Fan F Chen Zhaohong Z Zheng Chunxia C Li Jing J Zen Ke K Liu Zhihong Z Li Limin L

Cell death & disease 20220329 3

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 M ...[more]

PMID: 35351877

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Project description:BackgroundThe onset and progression of membranous nephropathy (MN) have been associated with complement activation, yet the overall characteristics of this activation in the kidneys remain unclear. In our study, we utilized urine proteomic data to investigate the features of complement activation. We examined the relationship between urine complement components and both clinicopathological features and clinical outcomes in patients with MN.MethodsDifferential expression proteins (DEPs) analysis was performed using proteomic data from urine samples collected from 50 patients with MN, 50 patients with IgA nephropathies (IgAN), and 72 healthy controls (HC). Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were carried out on the DEPs identified in MN. We further investigated the differentially expressed urinary complement proteins in MN patients, exploring their relationships with clinicopathological features and clinical remission. Next, 11 representative complements were selected for validation. Immunohistochemistry and immunofluorescence techniques were employed to compare the expression of CD59 and C5b-9 in renal tissues from MN patients, with analyses conducted on both the clinical remission group and the no remission group (n = 6 in each group).ResultsTotal 1,427 differentially expressed proteins were identified between the MN and HC groups. KEGG pathway analysis showed significant enrichment of these DEPs in the complement-activated pathway within the MN group. Additionally, a correlation was found between proteinuria and the levels of 27 urinary complement proteins. Notably, Collectin12 (collec12) and C1s were positively correlated with tubular atrophy/interstitial fibrosis (TIF) and monocyte infiltration. Furthermore, urine CD59 emerged as a predictor of clinical remission. Lower deposition of C5b-9 in renal tissue and higher expression of CD59 were detected in clinical remission group than non-remission group.ConclusionIn patients with MN, abnormal levels of complement components in urine are commonly observed. Currently, the use of complement inhibitors has brought new hope for the treatment of MN. The factor B inhibitor LNP023 and the factor D inhibitor BCX9930 are undergoing clinical trials for the treatment of MN. Our study indicates that complement abnormalities could serve as clinical biomarkers for tracking the progression of MN, predicting clinical remission, and guiding targeted complement therapy for those affected.

Project description:IntroductionMembranous nephropathy (MN) is a common cause of adult nephrotic syndrome that progresses to end-stage kidney disease in up to 40% of cases. It is an autoimmune disease characterized by glomerular subepithelial deposits containing IgG. In experimental MN, these deposits activate complement and cause kidney damage. The role of complement in human MN is less clearly defined. To address this, the current study focused on the role of complement in 2 independent primary (p) MN cohorts.MethodsGlomeruli were isolated by laser capture microdissection and analyzed by mass spectrometry, focusing on complement proteins, from kidney biopsy specimens from a pMN cohort (n = 11) and from normal controls (n = 5). Immunohistological staining of kidney biopsy specimens for complement proteins was also done. In a second pMN cohort (n = 13), urine levels of Ba, C5a, and C5b-9 (membrane attack complex [MAC]) were measured.ResultsMass spectrometry identified 8 complement pathway components (C1q, C3, C4, C5, C6, C7, C8, and C9) and 5 complement regulators (complement receptor type 1 [CR1], factor H [FH], FH-related protein 2 [FHR2], vitronectin, and clusterin). All complement levels were significantly higher in the MN groups than in the control group, except the level of CR1, which was lower. All pMN biopsy specimens showed negative or trace staining for C1q, positive staining for C3 and C4, and positive staining for at least 1 component of the lectin pathway. Urine Ba, C5a, and MAC were present in pMN, and their levels correlated (r Ba,C5a = 0.87, r Ba,MAC = 0.89, and r C5a,MAC = 0.97, P = .001 for each correlation).ConclusionElevated glomerular levels of C3, C4, and components of MAC (C5b-9) and absent or decreased levels of the complement regulator CR1, along with increased levels of complement activation products in the urine, support the involvement of complement in the pathogenesis of MN. These data raise the possibility that anti-complement therapies may be effective in some forms of MN.

Dataset Information

Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction.

Publications

Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction.

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