GDF-15 and NETosis Cross-Talk in Diabetes-Induced Renal and Cardiovascular Complications: Unraveling the Molecular Interactions
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Slika, Amani Wissam, American University of Beirut, Beirut, Lebanon
- Salameh, Elio, American University of Beirut, Beirut, Lebanon
- Abourjeili, Joseph, American University of Beirut, Beirut, Lebanon
- Sfeir, Ghiwa, American University of Beirut, Beirut, Lebanon
- Eid, Assaad Antoine, American University of Beirut, Beirut, Lebanon
Diabetic kidney disease (DKD) and diabetic cardiomyopathy (DCM) are severe complications of diabetes, posing significant risks of renal failure and cardiovascular events. One potential biomarker with promising implications in this context is growth differentiation factor 15 (GDF-15), a cytokine belonging to the transforming growth factor-β (TGF-β) family. Elevated levels of GDF-15 are observed in the presence of tissue injury, inflammation, and stress. Moreover, our research group has focused on exploring the relationship between neutrophil extracellular trap formation (NETosis) and the progression of injury in DKD and DCM. This article aims to elucidate the role and interplay between GDF-15 and NETosis in the development of renal and cardiac injury induced by type 2 diabetes.
T2DM was induced in C57BL/6J male black mice using the high fat diet/STZ model in two sets of experiments. In the first set, mice were divided into control, PMA-induced NETosis, T2D, and T2D treated with CLA (NETosis inhibitor) groups. In the second set, control mice, GDF-15 antibody AV-380-treated control mice (at 7.5mg/kg or 20mg/kg), T2D mice, and AV-380-treated T2D mice (at 7.5mg/kg or 20mg/kg) were utilized. Functional, histopathological, and molecular studies were performed on kidney and heart tissues from all groups.
Our data demonstrate that inhibiting GDF-15 with AV-380 or NETosis with CLA can restore renal and cardiac homeostasis in T2D mice. This is evident through reduced proteinuria, glomerulosclerosis, collagen deposition in the kidneys and heart, as well as improved cardiac ejection fraction and decreased inflammatory markers in the treated diabetic mice. Importantly, NETosis inhibition attenuated the diabetes-induced overexpression of GDF-15 in kidney and heart tissues, suggesting a crosstalk between these 2 signaling molecules. Intriguingly, inducing NETosis in control mice using PMA resulted in similar renal and heart injuries observed in diabetes.
Our study findings provide valuable insights into the role and interplay between GDF-15 and NETosis in diabetes-related cardiac and kidney injury. Targeting the GDF-15/NETosis signaling cascade through pharmacological interventions offers a basis for future clinical studies that aim to manage diabetes-associated complications.