Yiming Li
MS
Zhongnan Hospital of Wuhan University
Wuhan, United States
Disclosure information not submitted.
Yiming Li
MS
Zhongnan Hospital of Wuhan University
Wuhan, United States
Disclosure information not submitted.
Zhiyong Peng
Prof.
Zhongnan Hospital of Wuhan University
Wuhan, Pennsylvania, United States
Disclosure information not submitted.
Title: Transcription profiling of septic acute kidney injury identified TIFA regulated pyroptosis
Sepsis is the leading cause of acute kidney injury(AKI), and specific treatment options for septic AKI are very limited. Here, we use bulk RNA sequencing of sepsis model of AKI to characterize mRNA profile during acute kidney injury. A total of 298 differentially expressed genes (DEGs) were identified in kidneys with sepsis-induced injury. Bioinformatics analysis, including Gene Ontology (GO), metabolite-protein interactions (MPIs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, revealed that the DEGs mainly participate in the inflammatory response and metabolic processes. Analysis of comprehensive mRNA-seq data sets revealed the sepsis-induced AKI-specific cohorts of expressed genes, and six DEGs were tested in the urine from septic patients with/without AKI. TIFA and FASN were differently expressed in the urine from sepsis-induced AKI. Furthermore, we identified that TIFA is significantly upregulated in mouse kidney tissue following cecal ligation and puncture (CLP). We sought to investigate its role in LPS (TLR4 ligand) and ODN (TLR9 ligand) treated human kidney cells. TIFA triggered pyroptosis by activating the mitochondrial intrinsic apoptotic pathway. To further investigate the role of TIFA in sepsis, TIFA siRNA was transfected into HK-2 cells. Exposure of HK-2 cells to LPS and ODN caused disruption of mitochondrial transmembrane potential as evidenced by an increase in the proportion of cells with green fluorescence and a decrease in the proportion of cells with red JC-1 fluorescence. Knockdown of TIFA resulted in the decrease of the percentage of annexin V negative and PI positive cells after ODN treatment. GSDMD and Caspase-1 were also decreased when si-TIFA was transferred into HK-2 cells following LPS and ODN treatment. Suppression of TIFA by siRNA reduced the expression of cytokines (IL-1 and IL-18). These results demonstrated that TIFA induced pyroptosis in HK-2 by activating the mitochondrial intrinsic apoptotic pathway. Our study provides a detailed description of cellular responses after sepsis and suggests that the TIFA may represent a therapeutic target to improve sepsis induced kidney injury. The comprehensive characterization of kidney injury after sepsis provides a valuable resource for determining the underlying pathophysiology of human AKI.