Abstract: SA-PO0325
LXR Signaling Controls Complement-Mediated NETosis: A New Therapeutic Target in Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Hamade, Sarah, American University of Beirut, Beirut, Lebanon
- Almoussawi, Sarah, American University of Beirut, Beirut, Lebanon
- Alkhansa, Sahar, American University of Beirut, Beirut, Lebanon
- Njeim, Rachel, University of Miami Miller School of Medicine, Miami, United States
- El Danaf, Ghaith S., American University of Beirut, Beirut, Lebanon
- Dia, Batoul, American University of Beirut, Beirut, Lebanon
- KFoury, Hala M., American University of Beirut Medical Center Department of Pathology and Laboratory Medicine, 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, Lebanon
Background
Diabetic kidney disease (DKD) is a progressive microvascular complication of diabetes and a leading cause of end-stage renal failure. Despite advances in understanding its pathology, current therapies do not sufficiently address the innate immune components driving kidney injury. Both complement activation and neutrophil extracellular trap (NET) formation have been implicated in DKD, but the metabolic triggers linking them remain undefined. Liver X receptors (LXRs), nuclear receptors involved in lipid metabolism and inflammation, have not been explored in this context.
Methods
Male C57BL/6J mice were rendered diabetic using a high-fat diet and low-dose streptozotocin. In our study mice were divided into control, type 2 diabetes (T2D), and T2D treated with the LXR agonist DMHCA (80 mg/kg). A parallel group received Cl-amidine, a NETosis inhibitor. Renal function, histology, and immune markers were analyzed.
Results
T2D mice showed significant reduction in renal LXRα expression, along with marked upregulation of complement effectors C3a and C5a, increased NOX4-induced oxidative stress, and enhanced NETs formation. These changes coincided with albuminuria and glomerular damage. DMHCA treatment restored LXRα, suppressed C3a/C5a and NOX4 levels, inhibited NETosis, and improved renal outcomes. Cl-amidine provided comparable protection, validating NETs as effectors downstream of complement.
Conclusion
This study identifies a previously unrecognized immunometabolic axis in DKD, in which hyperglycemia suppresses LXR signaling, leading to complement activation, NOX4-mediated oxidative stress, and NETosis. These findings establish a mechanistic link between metabolic dysfunction and innate immunity in DKD and suggest that targeting LXR may represent a novel therapeutic strategy.