Abstract: TH-PO0261
Neutrophil Extracellular Traps Trigger Ferroptosis in Glomeruli of ANCA-Associated Vasculitis by Activating Heparanase-Mediated Syndecan-1 Shedding
Session Information
- Glomerular Diseases: Cell Biology
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Bai, Linkun, Peking Union Medical College Hospital, Beijing, China
- Zhang, Shuo, Peking Union Medical College Hospital, Beijing, China
- Chen, Xin, Peking Union Medical College Hospital, Beijing, China
- Hou, Fangxing, Peking Union Medical College Hospital, Beijing, China
- Ji, Peili, Peking Union Medical College Hospital, Beijing, China
- Shi, Xiaoxiao, Peking Union Medical College Hospital, Beijing, China
- Xia, Peng, Peking Union Medical College Hospital, Beijing, China
- Chen, Limeng, Peking Union Medical College Hospital, Beijing, China
Background
Neutrophil extracellular traps(NETs)contribute to kidney injury in ANCA-associated vasculitis(AAV)by damaging glomeruli,yet the regulatory mechanisms remain unclear.Given our previous finding that differentially expressed genes associated with AAV renal involvement were enriched in pathways related to glycocalyx interactions,among which SDC-1 is a major component.This study aimed to determine whether SDC-1 serves as a key molecular bridge in NETs-induced glomerular injury and to elucidate the underlying mechanism.
Methods
Prospectively recruit active AAV patients(n=23),AAV patients in remission(n=24),and healthy controls(n=30)for plasma collection.AAV rat models were established by daily oral administration of PTU and intraperitoneal injection of PMA on day 0 and day 7,while intervention groups were established by intraperitoneal injection of a DNase I every other day starting on day 11 of modeling.The rats were sacrificed on the 30th day after modeling.In vitro,NETs generated by neutrophils from active AAV patients were applied to HRGECs,with intervention groups treated with Dnase-I and HPSE inhibitor.
Results
In patients with active AAV,the main component of NETs and SDC-1 expression were significantly elevated and positively correlated (r=0.5545,P<0.0001).Both are closely related to disease activity and renal function damage(Scr[r=0.6537,P<0.0001],ESR[r =0.4829,P<0.0001], CRP[r=0.6356,P<0.0001]).Across AAV models,excessive renal NETs formation was accompanied by glycocalyx damage and ferroptosis,whereas therapeutic use of Dnase-I reduced NETs infiltration,decreased SDC-1 shedding, and inhibited ferroptosis.HPSE,an enzyme that specifically cleaves glycan side chains,showed an increase in expression,while SDC-1 and GPX4 expression decreased.The levels of SDC-1 and the cell injury factor ICAM-1 in the cell supernatant were elevated.Further intervention with Dnase-I and HPSE inhibitor showed that glycocalyx damage was reduced(Western blot of SDC-1 protein improved by 36.8% and 32.4%,respectively),ferroptosis was inhibited(Western blot of GPX4 protein improved by 53.1% and 25.5%,respectively),and cell injury was improved.
Conclusion
We identified that target NETs and HPSE could abolish the injury of endothelial glycocalyx integrity and ferroptosis of glomerular endothelial cells,shedding light on a new strategy for AAV therapy marked by SDC-1.