GDF-15 Is a Novel Therapeutic Target for Diabetes-Induced Kidney and Cardiac Injuries in Preclinical Models of Type 2 Diabetes (T2D)

Background: Diabetic kidney disease (DKD) and diabetic cardiomyopathy (DCM) are severe complications of diabetes, with poorly understood underlying mechanisms. GDF-15, a cytokine belonging to the transforming growth factor-β family, has been recently proposed as a novel biomarker for diabetic complications. Several clinical studies have shown that elevated GDF-15 expression is associated with the development of DKD and DCM. However, the pre-clinical role of GDF-15 as a risk predictor requires further investigation. We have previously shown NETosis, a specialized form of neutrophil-specific cell death, to be involved in the pathogenesis of diabetes. In this study, we examine the role of GDF-15 and its effect on NETs formaion in the development of renal and cardiac injuries associated with type 2 diabetes (T2D). Methods: Male C57BL/6J mice were used. T2D was induced using a high-fat diet/STZ protocol (DiaComp). Two sets of experiments were conducted. In the first series, mice were categorized into: control mice, GDF-15 antibody (AV-380)-treated control mice (at 7.5mg/kg or 20mg/kg), T2D-induced mice, and AV-380-treated T2D mice (at 7.5mg/kg or 20mg/kg). Short-term treatment was administered for 8 weeks. The second series of experiments included control mice, T2D mice, and AV-380-treated T2D mice (at 7.5mg/kg or 20mg/kg) with long-term treatment administered for 15 weeks. Functional, histopathological, and molecular studies were performed. Results: Our data show that inhibiting GDF-15 restores renal and cardiac homeostasis in T2D mice. Both short and long term treatments reduced proteinuria, glomerulosclerosis, collagen deposition in the kidneys and heart, as well as improved cardiac ejection fraction in AV-380 treated diabetic mice. The expression levels of prominent inflammatory markers were decreased. Furthermore, increased expression of the cardiac hypertrophic proteins and the reduced expression of cardioprotective markers associated with diabetes were restored following AV-380 treatment. Additionally, GDF-15 inhibition reduced the expression of NETosis markers. Conclusion: The findings of this study suggest that GDF-15 is a therapeutic target in diabetes-induced cardiac and kidney injuries.