{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:53:30Z","timestamp":1792788810971,"version":"4.5.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","funder":[{"name":"Capital's Funds for Health Improvement and Research","award":["2024-2-4076"],"award-info":[{"award-number":["2024-2-4076"]}]},{"name":"Beijing Natural Science Foundation","award":["7242143"],"award-info":[{"award-number":["7242143"]}]},{"name":"National Natural Science Foundation of China Youth Science Fund Project","award":["82500849"],"award-info":[{"award-number":["82500849"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National High Level Hospital Clinical Research Funding","award":["2024IR42"],"award-info":[{"award-number":["2024IR42"]}]},{"name":"Peking University First Hospital Cross-Research Project","award":["2023IR35"],"award-info":[{"award-number":["2023IR35"]}],"id":[{"id":"https:\/\/ror.org\/02z1vqm45","id-type":"ROR","asserted-by":"crossref"}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2019-I2M-5-046"],"award-info":[{"award-number":["2019-I2M-5-046"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2026,10]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Neutrophil extracellular trap biomarkers were elevated and correlated with disease activity and complement deposition in thrombotic microangiopathy.<\/jats:p>\n <\/jats:list-item>\n \n Inhibiting neutrophil extracellular traps reduced organ injury and complement deposition through CD59 shedding in glomerular endothelial cells.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n Complement hyperactivation and endothelial cell damage are pivotal pathogenic drivers of multiple organ damage in complement-mediated thrombotic microangiopathy (TMA). The specific pathogenic role of neutrophil extracellular traps (NETs) remains unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n This study included 107 patients with complement-mediated TMA and measured circulating and renal NET biomarkers. The effects of peptidylarginine deiminase 4 (\n Pad4<\/jats:italic>\n ) knockout, NET inhibitors (deoxyribonuclease I or GSK484), and neutrophil depletion were evaluated for their ability to attenuate multiorgan injury in complement-mediated TMA mice with a point mutation (W1206R) in complement factor H (FH\n R\/R<\/jats:sup>\n ). Furthermore, the influence of NETs on the regulation of the membrane attack complex (MAC), with a focus on CD59 modulation, was investigated in cultured human renal glomerular endothelial cells (HRGECs) and human umbilical vein endothelial cells.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Elevated levels of NET biomarkers in both plasma and kidney tissues were observed in complement-mediated TMA patients, which were associated with disease activity and increased MAC deposition. In FH\n R<\/jats:sup>\n \/R<\/jats:sup>\n mice,\n Pad4<\/jats:italic>\n knockout improved survival and attenuated phenotypes of TMA, as evidenced by the amelioration of anemia, kidney injury, MAC deposition, and macrovascular thrombosis. Therapeutic targeting of NETs with deoxyribonuclease I and PAD4 inhibitor GSK484 similarly ameliorated kidney pathology and MAC deposition in FH\n R\/R<\/jats:sup>\n mice. Neutrophil depletion significantly reduced systemic and kidney injury in FH\n R\/R<\/jats:sup>\n mice. NETs induced MAC deposition on HRGECs by promoting CD59 shedding through neutrophil serine proteases and enhanced coagulation through upregulation of tissue factor in human umbilical vein endothelial cells. Clinically, reduced glomerular CD59 expression and elevated urinary soluble CD59 levels were associated with both NET formation and MAC deposition.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Levels of NET biomarkers increased in complement-mediated TMA and drove multiorgan injury by shedding CD59 from HRGECs to enhance complement activation and participate in coagulation activation.<\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000001102","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T16:01:12Z","timestamp":1775577672000},"page":"2162-2175","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":2,"title":["Neutrophil Extracellular Traps Aggravate Injury in Complement-Mediated Thrombotic Microangiopathy"],"prefix":"10.1681","volume":"37","author":[{"given":"Xiao-tian","family":"Liu","sequence":"first","affiliation":[{"name":"Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, China"},{"name":"Research Units of Diagnosis and Treatment of lmmune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7345-4255","authenticated-orcid":false,"given":"Zi-xin","family":"Hua","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4793-6872","authenticated-orcid":false,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, China"},{"name":"Research Units of Diagnosis and Treatment of lmmune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Peking University International Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6413-6973","authenticated-orcid":false,"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, China"},{"name":"Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China"},{"name":"Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, Beijing, China"},{"name":"Research Units of Diagnosis and Treatment of lmmune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-5758","authenticated-orcid":false,"given":"Ying","family":"Tan","sequence":"additional","affiliation":[{"name":"Renal Division, Department of Medicine, Institute of Nephrology, Peking 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