GDF15 Aggravates Sepsis-Induced Coagulopathy and is Associated with PI3K/AKT/mTOR Signaling Changes

INTRODUCTION: The study was designed to explore the role of Growth Differentiation Factor 15 (GDF15) and its underlying mechanisms in coagulation dysfunction, the inflammatory response, and multi-organ damage using a rat model of cecal ligation and puncture (CLP)-induced sepsis. METHODS: A CLP-induced sepsis model was established in Sprague-Dawley rats. Adenovirus vectors were used to overexpress or knockdown GDF15. A PI3K inhibitor (LY294002) was administered to specific groups. Serum levels of GDF15, apoptosis markers (cleaved-caspase3), endothelial injury markers (syndecan-1, heparan sulfate), coagulation markers (D-dimer), inflammatory cytokines (IL-6, TNF-α), and PI3K/AKT/mTOR phosphorylation were measured by ELISA. Coagulation parameters and platelet counts were assessed. Organ damage was evaluated via H&E staining of the liver, heart, and kidneys. RESULTS: GDF15 levels were significantly elevated in CLP rats. High GDF15 levels were associated with increased cleaved-caspase3, syndecan-1, heparan sulfate, Ddimer, IL-6, and TNF-α; prolonged APTT, PT, and TT; decreased platelet count and fibrinogen (FIB); aggravated multi-organ damage; and enhanced PI3K, AKT, and mTOR phosphorylation. Silencing GDF15 or inhibiting PI3K with LY294002 reversed these effects, whereas GDF15 overexpression exacerbated them. The detrimental effects of GDF15 overexpression were attenuated by co-administration of LY294002. DISCUSSION: GDF15 exacerbates coagulopathy, inflammatory responses, and multiorgan damage in septic rats, likely by activating the PI3K/AKT/mTOR signaling pathway. These results establish GDF15 as a potential mediator of sepsis pathophysiology and a therapeutic target warranting further investigation. CONCLUSION: The findings of this study suggest that GDF15 is associated with coagulation dysfunction, inflammatory responses, and multi-organ injury in septic rats, and these effects may involve modulation of the PI3K/AKT/mTOR signaling pathway. Regarding translational implications, GDF15 has potential as a biomarker, but human validation is required. It may represent a potential therapeutic target that warrants further investigation, and its clinical relevance requires confirmation in human studies. It is important to emphasize that these findings are derived from a preclinical rat model and may not directly translate to human sepsis.