Anti-PLA2R antibodies promote endothelial pyroptosis and a procoagulant phenotype through FcγRI signaling

  • Nephrol Dial Transplant. 2026 May 13:gfag109. doi: 10.1093/ndt/gfag109.
Cai-Xia Lin  1 ,  Qi-Qi Ma  1  2 ,  Hui Lu  1  3 ,  Ping Wang  4 ,  Huang Kuang  1 ,  Miao Wang  1 ,  Yu Xiao  5 ,  Dong-Mei Xu  4 ,  Gao-Si Xu  2 ,  Ming-Hui Zhao  1 ,  Zhao Cui  1
Affiliations
  • 1. Renal Division, Peking University First Hospital, Beijing, China; Institute of Nephrology, Peking University, Beijing, China; Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China; Key Laboratory of Chronic Kidney Disease (CKD) Prevention and Treatment, Ministry of Education of China, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
  • 2. Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 3. Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
  • 4. Department of Nephrology, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Shandong, China.
  • 5. State Key Laboratory of Plant Diversity and Specialty Crops, Institute of Botany, the Chinese Academy of Sciences, Beijing, China.
PMID: 42127088 DOI: 10.1093/ndt/gfag109
Abstract

Background and hypothesis: Thromboembolism is a serious complication of nephrotic syndrome and occurs disproportionately in membranous nephropathy (MN). Whether anti-phospholipase A2 receptor (PLA2R) antibodies and complement activation directly promote endothelial dysfunction and thrombosis is unclear.

Methods: In a retrospective cohort of biopsy-proven MN (n=45 with thromboembolism; 1:2 time-selected controls), we quantified anti-PLA2R antibodies, C3a, and C5a and analyzed their associations with thromboembolic events. Using human umbilical vein endothelial cells (HUVECs), we tested MN plasma, purified anti-PLA2R IgG (including IgG4), and IgG fragments, and interrogated Fc and Complement Receptor pathways. Readouts included pro/anti-coagulant factor expression, inflammasome/Pyroptosis activation, and secreted mediators.

Results: Anti-PLA2R levels were higher in patients with thromboembolism than in those without and correlated with D-dimer and fibrin degradation products. A ROC-derived threshold of 92RU/mL was associated with greater thromboembolic risk. MN plasma and anti-PLA2R IgG induced a dose- and time-dependent procoagulant phenotype in HUVECs, upregulating tissue factor (TF), ICAM-1, and PAI-1 and increasing supernatant TF and sICAM-1. The Fc fragment reproduced these effects, whereas F(ab')2 did not. Anti-PLA2R colocalized with FcγRI; FcγRI silencing abrogated procoagulant responses and reduced NLRP3, Caspase-1 p20, GSDMD-N, IL-1β, and IL-18. The NLRP3 Inhibitor similarly suppressed Pyroptosis and procoagulant readouts. Complement anaphylatoxins C3a/C5a further increased TF/ICAM-1 via C3aR/C5aR, and antagonists reversed MN-plasma-induced effects.

Conclusions: Anti-PLA2R antibodies promote endothelial Pyroptosis and a TF-high procoagulant phenotype through FcγRI signaling in vitro.Complement signaling amplifies this response. Targeting FcγRI-inflammasome pathways may mitigate thromboembolic risk in MN.

Keywords
anti-PLA2R antibody; complement; endothelial cells; membranous nephropathy; thromboembolism.
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