#3581 ACSS2-INDUCED FATTY ACID SYNTHESIS PROMOTES NLRP3 INFLAMMASOME AND PYROPTOSIS OF RENAL TUBULAR CELLS IN SEPSIS-INDUCED ACUTE KIDNEY INJURY

Abstract Background and Aims Cellular fatty acid metabolism was supposed to be tightly associated with immune responses. Pyroptosis is a form of programmed cell death dependent on the NLRP3 inflammasome activation. Previous studies have revealed that acyl-CoA synthetase 2 (ACSS2) promoted fatty acid synthesis under metabolic stress. However, whether ACSS2-mediated fatty acid metabolism can regulate pyroptosis and inflammatory responses of renal tubular cells in AKI remain unclear. Method lipopolysaccharide (LPS) was intraperitoneally injected to establish the sepsis mouse model, and in vitro HK-2 cell culture model was achieved by LPS stimulation. HE and PAS staining were carried out to evaluate pathological injury of kidneys in mice. The renal tissue immunostaining was conducted to detect IL-1β expression and macrophage distribution in kidney tissues of mice. Gene expression of inflammatory factors was evaluated by real-time PCR. Western Blot was conducted to the activation of the NLRP3 pathway and pyroptosis in vivo and in vitro. Results Here, we demonstrated that the expression of ACSS2 was significantly increased in the renal epithelial cells of mice with Lipopolysaccharide (LPS)-induced AKI when compared to wild-type mice. ACSS2 regulates NLRP3-mediated caspase-1 activation and IL-1β production through the stimulation of fatty acid synthase (FASN) in renal epithelial cells. The deletion of ACSS2 attenuated renal tubular pathological injury and inflammatory cell infiltration in an LPS-induced mouse model. Consistently, ACSS2-deficient mice displayed impaired FASN-mediated lipid synthesis and decreased IL-1β production in response to the LPS challenge. In HK-2 cells, ACSS2 deficiency suppressed NLRP3-mediated caspase-1 activation and decreased fatty acid synthesis through the downregulation of FASN. The treatment with the chemical inhibitor C75 suppressed NLRP3-mediated caspase-1 activation and pyroptosis of HK-2 cells under LPS treatment in renal tubular cells. Conclusion Our results suggested that ACSS2 regulated the NLRP3 inflammasome activation and pyroptosis by inducing the FASN-mediated fatty acid synthesis pathway in renal epithelial cells. These results identified ACSS2 as a potential therapeutic target in AKI.