USF2 Knockdown Downregulates THBS1 to Inhibit the TGF-β Signaling Pathway and Reduce Pyroptosis in Sepsis-Induced Acute Kidney Injury
BackgroundAcute kidney injury (AKI) is a serious complication of sepsis. This study was performed to explore the mechanism that THBS1 mediated pyroptosis by regulating TGF-β signaling pathway in sepsis-induced AKI.MethodsGene 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. qRT-PCR and ELISA were performed to detect expressions of THBS1, TNF-α, IL-1β, and IL-18 in
... L-18 in sepsis-induced AKI patients and healthy volunteers. 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. 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 pathway detected. The upstream transcription factor USF2 was knocked down in cells to explore it effect on sepsis-induced AKI.ResultsTHBS1 was 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, partially reversing changes in cell morphology. Mechanistically, USF2 promoted oxidative stress response by transcriptionally activating THBS1 to activate TGF-β/NLRP3/Caspase-1 signaling pathway and stimulate pyroptosis, and finally exacerbated sepsis-induced AKI.ConclusionsUSF2 knockdown downregulates THBS1 to inhibit TGF-β signaling pathway and reduce pyroptosis and further to ameliorate sepsis-induced AKI.