LAUSR

Sepsis is the leading cause of acute kidney injury (AKI), and specific treatment options for septic AKI are very limited. Here, we used bulk RNA sequencing of a septic model of AKI to characterize the mRNA profile during AKI. The differentially expressed genes (DEGs) mainly participate in the inflammatory response and metabolic processes. Analysis of comprehensive mRNA-seq datasets revealed sepsis-induced AKI-specific cohorts of expressed genes, and six DEGs were tested in urine from septic patients with/without AKI. TRAF-interacting protein with forkhead-associated domain (TIFA) and fatty acid synthase (FASN) were differentially expressed in the urine from the sepsis-induced AKI group. Furthermore, we found that TIFA expression was significantly upregulated in mouse kidney tissue following cecal ligation and puncture (CLP). We sought to investigate its role in lipopolysaccharide (LPS) (TLR4 ligand)- and oligodeoxynucleotides (ODN) (TLR9 ligand)-treated human kidney cells and mouse. TIFA was located in Lotus tetragonolobus lectin (LTL) positive renal cells in kidney tissue, which was stained by immunofluorescence. Exposure of HK-2 cells to LPS and ODN caused disruption of the mitochondrial transmembrane potential. The results of transmission electron microscope (TEM) showed that mitochondrial damages were improved in TIFA-knockdown group. Moreover, knockdown of TIFA resulted in a decrease in the percentage of annexin V-positive and PI-negative cells after ODN treatment. The protein of NLRP3, Caspase-1 and GSDMD were also decreased when si-TIFA was transferred into HK-2 cells following LPS and ODN treatment. Activation of TIFA enhanced the expression of IL-1β and IL18. These results indicated that TIFA induced pyroptosis by activating the mitochondrial damage. Our study provides a detailed transcriptomic description of the renal cellular responses after sepsis. Our study suggest that TIFA is involved in pyroptosis by activating the mitochondrial damage and may be a therapeutic target to treat sepsis-induced kidney injury.