Study On The RELATIONSHIP Between The USF2/THBS1 Axis In The Regulation Of Pyroptosis And The Sepsis-induced Acute Kidney Injury

Objective: Acute kidney injury(AKI)is a serious complication of sepsis.This study was performed to explore the mechanism that THBS1 mediated pyroptosis by regulating the TGF-β signaling pathway in sepsis-induced AKI.Methods: Gene expression microarray related to sepsis-induced AKI was obtained from the GEO database,and the mechanism in sepsis-induced AKI was predicted by bioinformatics analysis.q RT-PCR and ELISA were performed to detect expressions of THBS1,USF2,TNF-α,IL-1β,and IL-18 in sepsis-induced AKI patients and healthy volunteers.The mouse model of sepsis-induced AKI was established,with serum creatinine,urea nitrogen,24-h urine output measured,and renal tissue lesions observed by HE staining.The cell model of sepsis-induced AKI was cultured in vitro,with expressions of TNF-α,IL-1β,and IL-18,pyroptosis,Caspase-1 and GSDMD-N,and activation of TGF-β/Smad3 pathway detected.The upstream transcription factor USF2 was knocked down in cells to explore its effect on sepsis-induced AKI.Results: THBS1 and USF2 were highly expressed in patients with sepsis-induced AKI.Silencing THBS1 protected mice against sepsis-induced AKI,and significantly decreased the expressions of NLRP3,Caspase-1,GSDMD-N,IL-1β,and IL-18,increased cell viability,and decreased LDH activity,thus partially reversing the changes in cell morphology.Mechanistically,USF2 promoted oxidative stress responses by transcriptionally activating THBS1 to activate the TGF-β/Smad3/NLRP3/Caspase-1 signaling pathway and stimulate pyroptosis,and finally exacerbated sepsis-induced AKI.Conclusion: USF2 knockdown downregulates THBS1 to inhibit the TGF-β/Smad3 signaling pathway and reduce pyroptosis and further ameliorate sepsis-induced AKI.