Daoyuan Lv, Song Jiang, Mingchao Zhang, Xiaodong Zhu, Fan Yang, Hui Wang, Shen Li, Feng Liu, Caihong Zeng, Weisong Qin, Limin Li, Zhihong Liu
{"title":"双硫仑通过抑制足细胞焦亡治疗膜性肾病。","authors":"Daoyuan Lv, Song Jiang, Mingchao Zhang, Xiaodong Zhu, Fan Yang, Hui Wang, Shen Li, Feng Liu, Caihong Zeng, Weisong Qin, Limin Li, Zhihong Liu","doi":"10.1159/000524164","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Membranous nephropathy (MN) is a common chronic kidney disease in adults and a major challenge of clinical practice for its treatment. Despite major advances, since the discovery of the phospholipase A2 receptor as the major autoantigen of podocytes in MN, the mechanisms leading to glomerular damage remain elusive. Pyroptosis, a newly discovered type of programed necrotic cell death mainly mediated by gasdermin, was found to be responsible for podocyte injury in MN in our recent work.</p><p><strong>Objectives: </strong>The aim of this study was to explore the therapeutic effect of an FDA-approved drug, disulfiram (DSF), in the treatment of MN by inhibiting pyroptosis.</p><p><strong>Methods and results: </strong>DSF significantly alleviated C3a/C5a-induced podocyte injury in vitro and renal lesions in passive Heymann nephritis (PHN) rats, as reflected by the decreased percentage of propidium iodide staining podocytes, decreased lactate dehydrogenase release from cultured podocytes and improvement in 24-h urine protein, serum albumin, serum creatinine, abnormal alterations of podocyte injury markers Desmin and WT-1 and podocyte foot process fusion in PHN rats. The protective effect of DSF on podocyte injury in vitro and in vivo can be ascribed to its inhibition of the activation and membrane translocation of the pyroptosis executor gasdermin D (GSDMD) in podocytes. DSF also inhibited the increase and activation of the pyroptosis signaling pathway NLRP3-ASC-Caspase-1/IL-18/GSDMD in C3a/C5a-treated podocytes and renal tissue of PHN rats.</p><p><strong>Conclusion: </strong>DSF is a potential drug for MN treatment, and its clinical application needs to be further investigated.</p>","PeriodicalId":17830,"journal":{"name":"Kidney Diseases","volume":"8 4","pages":"308-318"},"PeriodicalIF":3.2000,"publicationDate":"2022-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/71/90/kdd-0008-0308.PMC9386405.pdf","citationCount":"2","resultStr":"{\"title\":\"Treatment of Membranous Nephropathy by Disulfiram through Inhibition of Podocyte Pyroptosis.\",\"authors\":\"Daoyuan Lv, Song Jiang, Mingchao Zhang, Xiaodong Zhu, Fan Yang, Hui Wang, Shen Li, Feng Liu, Caihong Zeng, Weisong Qin, Limin Li, Zhihong Liu\",\"doi\":\"10.1159/000524164\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Membranous nephropathy (MN) is a common chronic kidney disease in adults and a major challenge of clinical practice for its treatment. Despite major advances, since the discovery of the phospholipase A2 receptor as the major autoantigen of podocytes in MN, the mechanisms leading to glomerular damage remain elusive. Pyroptosis, a newly discovered type of programed necrotic cell death mainly mediated by gasdermin, was found to be responsible for podocyte injury in MN in our recent work.</p><p><strong>Objectives: </strong>The aim of this study was to explore the therapeutic effect of an FDA-approved drug, disulfiram (DSF), in the treatment of MN by inhibiting pyroptosis.</p><p><strong>Methods and results: </strong>DSF significantly alleviated C3a/C5a-induced podocyte injury in vitro and renal lesions in passive Heymann nephritis (PHN) rats, as reflected by the decreased percentage of propidium iodide staining podocytes, decreased lactate dehydrogenase release from cultured podocytes and improvement in 24-h urine protein, serum albumin, serum creatinine, abnormal alterations of podocyte injury markers Desmin and WT-1 and podocyte foot process fusion in PHN rats. The protective effect of DSF on podocyte injury in vitro and in vivo can be ascribed to its inhibition of the activation and membrane translocation of the pyroptosis executor gasdermin D (GSDMD) in podocytes. DSF also inhibited the increase and activation of the pyroptosis signaling pathway NLRP3-ASC-Caspase-1/IL-18/GSDMD in C3a/C5a-treated podocytes and renal tissue of PHN rats.</p><p><strong>Conclusion: </strong>DSF is a potential drug for MN treatment, and its clinical application needs to be further investigated.</p>\",\"PeriodicalId\":17830,\"journal\":{\"name\":\"Kidney Diseases\",\"volume\":\"8 4\",\"pages\":\"308-318\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2022-05-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/71/90/kdd-0008-0308.PMC9386405.pdf\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Kidney Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1159/000524164\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/7/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Kidney Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1159/000524164","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/7/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
Treatment of Membranous Nephropathy by Disulfiram through Inhibition of Podocyte Pyroptosis.
Introduction: Membranous nephropathy (MN) is a common chronic kidney disease in adults and a major challenge of clinical practice for its treatment. Despite major advances, since the discovery of the phospholipase A2 receptor as the major autoantigen of podocytes in MN, the mechanisms leading to glomerular damage remain elusive. Pyroptosis, a newly discovered type of programed necrotic cell death mainly mediated by gasdermin, was found to be responsible for podocyte injury in MN in our recent work.
Objectives: The aim of this study was to explore the therapeutic effect of an FDA-approved drug, disulfiram (DSF), in the treatment of MN by inhibiting pyroptosis.
Methods and results: DSF significantly alleviated C3a/C5a-induced podocyte injury in vitro and renal lesions in passive Heymann nephritis (PHN) rats, as reflected by the decreased percentage of propidium iodide staining podocytes, decreased lactate dehydrogenase release from cultured podocytes and improvement in 24-h urine protein, serum albumin, serum creatinine, abnormal alterations of podocyte injury markers Desmin and WT-1 and podocyte foot process fusion in PHN rats. The protective effect of DSF on podocyte injury in vitro and in vivo can be ascribed to its inhibition of the activation and membrane translocation of the pyroptosis executor gasdermin D (GSDMD) in podocytes. DSF also inhibited the increase and activation of the pyroptosis signaling pathway NLRP3-ASC-Caspase-1/IL-18/GSDMD in C3a/C5a-treated podocytes and renal tissue of PHN rats.
Conclusion: DSF is a potential drug for MN treatment, and its clinical application needs to be further investigated.
期刊介绍：
''Kidney Diseases'' aims to provide a platform for Asian and Western research to further and support communication and exchange of knowledge. Review articles cover the most recent clinical and basic science relevant to the entire field of nephrological disorders, including glomerular diseases, acute and chronic kidney injury, tubulo-interstitial disease, hypertension and metabolism-related disorders, end-stage renal disease, and genetic kidney disease. Special articles are prepared by two authors, one from East and one from West, which compare genetics, epidemiology, diagnosis methods, and treatment options of a disease.
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