Growth Differentiation Factor (GDF-15) as a Major Player in Diabetes-Induced Renal and Cardiovascular Injuries: A Mechanistic Approach

Abstract

Introduction: Diabetes, being a major cause of morbidity worldwide, can simultaneously cause renal (Diabetic Kidney Disease) and cardiac dysfunction. Recent data suggest that in the presence of tissue injury, inflammation, and stress conditions, circulating levels of a transforming growth factor-β (TGF-β) related cytokine termed Growth differentiation factor-15 (GDF-15) increase dramatically. Also, GDF-15 has been currently suggested to be a biomarker in type 2 diabetes as well as in cardiac injury and renal dysfunction. Yet, its role in diabetes-induced microvascular and macrovascular complications remains poorly investigated. Besides, our group and others have previously identified NETosis, a novel form of neutrophil-specific cell death, to play a pivotal role in the pathogenesis of diabetes. Furthermore, recent studies suggested that GDF-15 can regulate neutrophil arrest and counteract its recruitment. However, a direct causal link between GDF-15 and NETosis and the role of their crosstalk in diabetes-induced complications remain to be elucidated. In addition, the mTOR signaling pathway, a major player in diabetes-induced renal and cardiac complications, is downregulated in GDF-15 transgenic mice. These findings suggest a potential crosstalk between GDF-15 and mTOR pathway, that warrants to be explored further in the context of diabetes-induced renal and cardiovascular events. Aim: In this study, we aim to assess the crosstalk between GDF-15, NETosis, and mTOR signaling pathway in diabetes-induced renal and cardiac injury. Methods: Control mice, mice treated with phorbol 12-myristate 13-acetate (PMA) to induce NETosis, and type 1 and type 2 diabetic mice treated either with Cl-amidine (CLA) to inhibit NETosis or with Cl-amidine’s vehicle were used. In parallel experiments, control mice, type 1 diabetic mice, and type1 diabetic mice models treated with rapamycin (mTORC-1 inhibitor), JR-AB2-011 (mTORC-2 inhibitor), or PR242 (mTORC-1/2 inhibitor) were used. Functional, histological, and molecular parameters of the left ventricle and the kidneys were determined. Results: Our results show that treatment with PMA or the induction of diabetes is associated with an increase in GDF-15 expression in the kidneys and left ventricle. Interestingly, treatment with CLA attenuates the diabetes-induced overexpression of GDF-15. These results imply that GDF-15 is upregulated in diabetes-induced renal and cardiovascular complications and highlight its role as a potential marker in diabetes-induced injury. Of interest, our data also suggest that NETs formation regulates the GDF-15 signaling pathway. Besides, our results show that the increase in the GDF-15 expression in diabetes was reversed upon the inhibition of mTORC1, mTORC2, or both mTORC 1/2 signaling pathways. These data highlight a potential crosstalk between mTOR and GDF-15 signaling pathways, which mediates renal and left ventricular injuries associated with diabetes. Taken together our findings show that the mTOR/NETosis/GDF15 signaling axis is a potential therapeutic target for diabetes-induced renal and left ventricular injuries. Conclusion: GDF-15, being a significant mediator in diabetes-induced complications, may be utilized in routine clinical practices for predicting mortality outcomes. Translational future studies may also involve the therapeutic implications of GDF-15 catalytic activity by small-molecule inhibitors or activators.