Saikosaponin-d Alleviates Renal Inflammation and Cell Apoptosis in a Mouse Model of Sepsis via TCF7/FOSL1/Matrix Metalloproteinase 9 Inhibition

Abstract

Evidence exists reporting that Saikosaponin-d can prevent experimental sepsis, and this study aims to illustrate the molecular events underlying its renoprotective effects on lipopolysaccharide (LPS)-induced renal inflammation simulating sepsis. Through network pharmacology analysis and bioinformatics analysis, we identified that saikosaponin-d may influence sepsis development by mediating TCF7. Dual luciferase reporter gene and ChIP assays were used to explore the interactions between TCF7, FOSL1 and MMP9. The experimental data suggested that Saikosaponin-d attenuated LPS-induced renal injury, as evidenced by reduced the production of proinflammatory cytokines as well as cell apoptosis in the renal tissues of LPS-induced mice. Mechanically, Saikosaponin-d inhibited FOSL1 by inhibiting TCF7, which reduced the expression of inflammatory factors in renal cells. TCF7 activated the FOSL1 expression and consequently promoted the expression of MMP9. Also, Saikosaponin-d reduced cell apoptosis and the expression of inflammatory factors by inhibiting the TCF7/FOSL1/MMP9 axis in vivo. In conclusion, Saikosaponin-d suppresses FOSL1 transcription by downregulating TCF7, thereby inhibiting MMP9 expression and ultimately reducing the renal inflammation and cell apoptosis induced by sepsis.