Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 41, Issue 10, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00332-21
Keywords
sepsis; renal inflammation; saikosaponin-d; TCF7; FOSL1; MMP9; apoptosis
Categories
Funding
- Zhejiang Provincial Medical and Health Science and Technology Program [2018243705, 2020KY909]
- Ningbo Medical Science and Technology Program [2019Y50]
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Saikosaponin-d (Sa) can alleviate LPS-induced renal inflammation and cell apoptosis by modulating the TCF7/FOSL1/MMP9 axis.
Evidence exists reporting that saikosaponin-d (Sa) 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 Sa may influence sepsis development by mediating TCF7. Dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays were used to explore the interactions between TCF7, FOSL1, and matrix metalloproteinase 9 (MMP9). The experimental data suggest that Sa attenuated LPS-induced renal injury, as evidenced by the reduced production of proinflammatory cytokines as well as cell apoptosis in the renal tissues of LPS-induced mice. Mechanically, Sa 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, Sa reduced cell apoptosis and the expression of inflammatory factors by inhibiting the TCF7/FOSL1/MMP9 axis in vivo. In conclusion, Sa suppresses FOSL1 transcription by downregulating TCF7, thereby inhibiting MMP9 expression and ultimately reducing the renal inflammation and cell apoptosis induced by sepsis.
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