Growth Differentiation Factor-15 (GDF-15) and Inflammation in Diabetic Kidney Disease: A Friend, A Foe, Or A Fellow Traveler.

Abstract

Introduction: Diabetes Mellitus is associated with several complications, among which is diabetic kidney disease (DKD). DKD is considered the strongest predictor of mortality in diabetic patients and the main cause of kidney failure worldwide. It has been shown that tissue injury, inflammation, and stress conditions in DKD are closely correlated with the circulating levels of transforming growth factor-β (TGF- β) related cytokine, also known as Growth Differentiation factor-15 (GDF-15). GDF-15 being a stress-responsive cytokine has been implicated in a variety of physiological and pathological processes. Recent studies have suggested that GDF-15 may play a role in the pathogenesis of DKD by modulating inflammatory responses in the kidney. A newly introduced monoclonal antibody; AV-380, has been developed to target GDF-15. It acts by specifically binding circulating GDF-15, blocking its interaction with its receptor and subsequent downstream signaling pathways. Collectively, this lead us to study the inflammatory role of GDF-15 in DKD.

Methods: C57BL/6J male black mice were allocated into 2 groups: a control group and a HFD+STZ induced type II diabetic group. These groups were further divided into 3 subgroups: group treated with saline, group treated with 7.5 mg/kg of AV-380, and a group treated with 20 mg/kg of AV380. Treatment lasted for a duration of 8 weeks. Functional, histopathological, biochemical and molecular studies were performed on kidney tissues from all groups. Results: Our results show that treatment with AV-380 significantly attenuated renal injury by inhibiting hyperglycemia-induced oxidative stress. AV-380 treatment ameliorates kidney injury and this was transduced functionally by a reduction in proteinuria. At the histological level, PAS and MT staining revealed reduced glomerulosclerosis and collagen deposition respectively. In addition, looking at the general inflammatory markers, we noticed a significant decrease in mRNA expression of IL-6, IL-23, IL-12, IL-1β and TNF-α upon treatment with AV-380 irrespective of dose. This suggests that GDF-15 may have a regulatory effect on the inflammatory status in DKD. To further delineate the mechanism by which AV-380 is regulating inflammation, we will be assessing a set of anti-inflammatory cytokines, as well as specific cell markers of immune cells namely macrophages and neutrophils. Conclusion: Our findings indicate a crosstalk between GDF-15 and inflammation in diabetes-induced renal injury. Pharmacological interventions aimed at manipulation of the GDF-15 signaling cascade in future studies may be beneficial in a clinical setting of diabetes-induced renal complications.