Abstract Body: Chronic kidney disease (CKD) affects millions worldwide and leads to significant morbidity and mortality, especially in patients with weight loss, but the underlying mechanisms remain poorly understood. Significant weight loss in CKD patients often predict worse outcomes and mortality. This project aims to investigate the role of the protein growth differentiation factor 15 (GDF15) in CKD progression and weight loss.
Gdf15 knockout (Gdf15^-/-) mice in adenine diet-induced CKD exhibited more pronounced renal dysfunction, including more inflammatory cell infiltration, glomerular necrosis, and tubular dilatation, but Gdf15^-/- mice were partially protected from CKD-associated weight loss. GDF15 receptor Gfral knockout mice (Gfral^-/-) were also partially protected from CKD-associated weight loss and exhibited worse renal function, suggesting GFRAL-dependent role of GDF15. Metabolic analysis revealed that the weight protection effects in Gdf15^-/- mice are primarily attributed to increased caloric intake but not energy expenditure. Mechanistically, RNA-seq data showed that Gdf15^-/- kidneys exhibited increased expression of immune response and extracellular matrix genes and decreased expression of metabolic genes, consistent with their worse kidney injury and function phenotype. Intriguingly, pair-fed Gdf15^-/- mice exhibited similar renal function and body weight loss to Gdf15^+/+ mice. Correlation analysis demonstrated that serum GDF15 level was positively correlated with kidney function indicators, BUN and Creatinine. Collectively, our data reveals loss of GDF15 protects CKD associated cachexia via promoting food intake.
Conclusion: This research provides critical insights into the role of GDF15-GFRAL signaling in CKD and indicates blocking GDF15-GFRAL signaling as a potential therapy to alleviate CKD-associated cachexia.