Abstract: FR-PO0311
GDF-15 Drives NETosis and Macrophage Polarization in Diabetic Kidney and Cardiac Injury: Dual-Organ Inflammatory Axis and Therapeutic Target
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Slika, Amani Wissam, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- Jomaa, Dalal Mohamad, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- Zaidan, Sarah, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- Yehya, Rita, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- Almoussawi, Sarah, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- Sfeir, Ghiwa, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- KFoury, Hala M., American University of Beirut Medical Center, Beirut, Beirut Governorate, Lebanon
- Njeim, Rachel, American University of Beirut, Beirut, Beirut Governorate, Lebanon
- Ziyadeh, Fuad N., American University of Beirut Medical Center, Beirut, Beirut Governorate, Lebanon
- Eid, Assaad Antoine, American University of Beirut, Beirut, Beirut Governorate, Lebanon
Background
Diabetic kidney disease (DKD) and diabetic cardiomyopathy (DCM) are major complications of type 2 diabetes (T2D) with persistent unmet clinical need. While newer therapies have improved outcomes, progression often continues. Growth differentiation factor-15 (GDF-15), a stress-inducible cytokine of the TGF-β superfamily, is elevated in DKD and DCM, yet its mechanistic role remains undefined. Inflammation is a critical driver of diabetes-induced organ injury. Neutrophil extracellular trap formation (NETosis) has recently emerged as a novel pathogenic pathway in several diseases. This study investigates the role of GDF-15 in modulating NETosis and macrophage polarization and examines the therapeutic potential of its inhibition in T2D.
Methods
Male C57BL/6J mice were rendered diabetic using a high-fat diet and low-dose streptozotocin. Mice were grouped into controls, AV-380 treated controls (7.5 or 20 mg/kg), T2D, and AV-380 treated T2D groups. Both short- (8 weeks) and long-term (15 weeks) treatment arms were included. Functional, histological, and molecular analyses were performed on renal and cardiac tissues.
Results
Pharmacological inhibition of GDF-15 with AV-380 improved renal and cardiac outcomes. It reduced proteinuria, glomerulosclerosis, and fibrosis, preserved cardiac ejection fraction, and normalized hypertrophic gene expression. AV-380 markedly suppressed NETosis (MPO, NE, Ly6g, CitH3) and promoted macrophage polarization toward an anti-inflammatory M2 phenotype (Arg1, Stat6, CCL17, CCL22), while downregulating M1 markers (iNOS, TNF-α, CD86, CxCl9, CxCl10).
Conclusion
These findings identify a conserved GDF-15-driven inflammatory axis involving NETosis and macrophage modulation in DKD and DCM. GDF-15 inhibition represents a novel adjunct strategy to mitigate diabetes-associated cardiorenal complications through a mechanism not targeted by current therapies.