Abstract: FR-PO0191
NOX4-Driven Complement Activation Promotes NETosis and Kidney Injury in Experimental Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Hamade, Sarah, American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon
- Almoussawi, Sarah, American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon
- Alkhansa, Sahar, American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon
- Dia, Batoul, American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon
- Njeim, Rachel, University of Miami Miller School of Medicine, Miami, Florida, United States
- El Danaf, Ghaith S., American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon
- KFoury, Hala M., American University of Beirut Medical Center, Beirut, Beirut Governorate, Lebanon
- Ziyadeh, Fuad N., American University of Beirut Medical Center, Beirut, Beirut Governorate, Lebanon
- Eid, Assaad Antoine, American University of Beirut Faculty of Medicine, Beirut, Beirut Governorate, Lebanon
Background
Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease despite current renoprotective therapies, highlighting the need to identify novel pathogenic mechanisms. Although oxidative stress, complement activation, and neutrophil extracellular traps (NETs) have each been implicated in DKD, their mechanistic interaction remains poorly understood. Here, we investigated, for the first time, the interplay between NOX4-mediated oxidative stress, complement activation, and NETosis as a unified inflammatory axis in DKD and evaluated the therapeutic effect of pharmacological NET inhibition.
Methods
Type 2 diabetes was induced using high-fat diet and low-dose streptozotocin. Mice were assigned to control, PMA-treated control (NET activator), T2DM, or T2DM treated with CLA (NET inhibitor). Renal injury, fibrosis, NETosis, oxidative stress, complement activation, and inflammation were assessed by biochemical, histologic, immunostaining, and molecular analyses including MPO-DNA complexes, neutrophil elastase, NOX4, C3/C3aR1, C5aR1/C5aR2, factor B, cytokines/chemokines, and immune cell infiltration. Correlation analyses were performed among oxidative stress, complement activation, NETosis, inflammation, and renal injury. Mechanistic studies were performed in high glucose-treated human podocytes with or without siNOX4 or C3 siRNA silencing.
Results
T2DM mice developed significant renal injury associated with increased NOX4 expression, oxidative stress, complement activation, and NETosis. PMA-treated mice showed increased NET formation and renal inflammation, supporting a pathogenic role for NETs in kidney injury. CLA treatment attenuated NETosis, inflammation, oxidative stress, complement activation, fibrosis, and podocyte injury. Preliminary integrative analyses suggest positive associations between NOX4 expression, complement activation, NETosis markers, and severity of renal injury, supporting the presence of a coordinated inflammatory signaling network in DKD. Ongoing mechanistic studies in human podocytes are expected to further define whether NOX4 and complement signaling directly regulate the pro-NETotic inflammatory microenvironment contributing to podocyte dysfunction.
Conclusion
These findings identify a NOX4-driven complement–NETosis axis contributing to DKD progression and highlight NETosis as a potential therapeutic target.