Growth Differentiation Factor-15 (GDF-15) as a Therapeutic Target in Type 2 Diabetes-Induced Kidney Injury

Abstract

Background: Diabetic kidney disease (DKD) is a serious complication of diabetes which poses a significant risk of renal failure. Understanding the underlying signaling mechanisms of DKD pathogenesis is crucial for effective management and treatment. Growth Differentiation Factor-15 (GDF-15), a cytokine belonging to the transforming growth factor-β (TGF-β) family has emerged as a new potential biomarker with promising implications in this context. In the presence of tissue injury, inflammation, and stress conditions, the levels of GDF-15 increase dramatically. Previous work from our group and others has highlighted the role of inflammatory processes particularly macrophage polarization and NETosis as key drivers of kidney injury. This study investigates the role of GDF-15 in modulating these pathways and its potential as a therapeutic target in T2D- related renal injury. Methods: Male C57BL/6J mice were employed. Type 2 diabetes (T2D) was induced using a high-fat diet/STZ protocol (Dia Comp). Two sets of experiments were conducted. In the first set, mice were categorized into 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). The second set included control mice, T2D, and T2D treated with CLA (NETosis inhibitor) groups. Various functional, histopathological, and molecular studies were performed. Results: Our data show that inhibiting GDF-15 with AV-380 or NETosis with CLA restores renal homeostasis in T2D mice. This is evident through reduced proteinuria, glomerulosclerosis, and collagen deposition in the kidneys of the treated diabetic mice. Additionally, inflammatory markers such as IL-6, IL-12, IL-23, and TNF-alpha were decreased. Importantly, GDF-15 inhibition had a pronounced impact on inflammation, as evidenced by a marked suppression of NETosis markers. Furthermore, AV-380 treatment shifted macrophage polarization demonstrating a significant decrease in M1 macrophage surface markers alongside enhanced activation of M2 macrophage markers. Intriguingly, CLA-mediated inhibition of NETosis also shifted macrophage polarization toward an anti-inflammatory M2 phenotype, reducing the prevalence of pro-inflammatory M1 macrophages. Conclusion: This study demonstrates that GDF-15 plays a central role in the pathogenesis of diabetes-induced renal injury, largely through its effects on NETosis and macrophage polarization. Targeting GDF-15 with AV-380 not only restores functional and structural integrity in the kidneys but also attenuates inflammation, highlighting its potential as a therapeutic target for managing diabetic complications.