The potential biomarker TIFA regulates pyroptosis in sepsis-induced acute kidney injury

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-1 beta 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.

Automated summary

This study conducted bulk RNA sequencing to analyze septic acute kidney injury (AKI), revealing differentially expressed genes (DEGs) mainly related to inflammatory response and metabolic processes. Further investigations identified TIFA and FASN as differentially expressed genes in the urine of sepsis-induced AKI patients. TIFA was found to activate pyroptosis through mitochondrial damage, suggesting its potential as a therapeutic target for sepsis-induced kidney injury.