USF2 knockdown downregulates THBS1 to inhibit the TGF-β signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury

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. 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. qRT-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. 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. USF2 knockdown downregulates THBS1 to inhibit the TGF-β/Smad3 signaling pathway and reduce pyroptosis and further ameliorate sepsis-induced AKI.