Molecular and Functional Significance of Growth Differentiation Factor-15: A Review on Cardiovascular-Kidney-Metabolic Biomarker

Abstract

Cardiovascular-kidney-metabolic (CKM) syndrome is the association between obesity, diabetes, CKD (chronic kidney disease), and cardiovascular disease. GDF-15 mainly acts through the GFRAL (Glial cell line-derived neurotrophic factor Family Receptor Alpha-Like) receptor. GDF-15 and GDFRAL complex act mainly through RET co-receptors, further activating Ras and phosphatidylinositol-3-kinase (PI3K)/Akt pathways through downstream signaling. GDF-15 decreases cardiac dysfunction and hypertrophy by inducing HIF-α (hypoxia-inducible factor-1α). It causes increased fractional shortening and a significant decrease in ventricular dilation through the induction of the SMAD 2/3. GDF-15 prevents hyperglycemia-induced apoptosis in diabetes mellitus. GDF-15 causes anorexia by influencing the central systems regulating metabolism and appetite. Therefore, targeting GDF-15 can be useful for the treatment of anorexia caused by cancer as well as the prevention of resulting weight loss. GDF-15 has an important role in predicting mortality in acute kidney injury. Its high levels are related to eGFR decline and also have a prognostic role in CKD patients. Growth differentiation factor-15 (GDF-15) is a vital biomarker for diagnosis, treatment, and prognosis of CKM syndrome. Elevated GDF-15 levels can be utilised as a biomarker to determine the suitable metformin dosage. In light chain amyloidosis, a raised level of GDF-15 predicts early death in heart failure and renal disease patients. In vivo, studies using GDF-15 analogs and antibodies against GFRAL to affect metabolic parameters and ventricular dilatation have shown potential for GDF-15-based therapeutic interventions. This review aims to study the role of GDF-15 in CKM syndrome and establish it as a CKM biomarker.