Li Yiming, Zhang Jing, Zhai Pan, Hu Chang, Suo Jinmeng, Wang Jing, Liu Chang, Peng Zhiyong
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China.
Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
Int Immunopharmacol. 2023 Feb;115:109580. doi: 10.1016/j.intimp.2022.109580. Epub 2022 Dec 29.
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.
脓毒症是急性肾损伤（AKI）的主要原因，而脓毒症相关性急性肾损伤的特异性治疗方案非常有限。在此，我们对急性肾损伤脓毒症模型进行了大量RNA测序，以表征急性肾损伤期间的mRNA谱。差异表达基因（DEGs）主要参与炎症反应和代谢过程。对综合mRNA-seq数据集的分析揭示了脓毒症诱导的急性肾损伤特异性表达基因队列，并在有/无急性肾损伤的脓毒症患者尿液中对6个差异表达基因进行了检测。含叉头相关结构域的TRAF相互作用蛋白（TIFA）和脂肪酸合酶（FASN）在脓毒症诱导的急性肾损伤组尿液中差异表达。此外，我们发现盲肠结扎和穿刺（CLP）后小鼠肾组织中TIFA表达显著上调。我们试图研究其在脂多糖（LPS）（TLR4配体）和寡脱氧核苷酸（ODN）（TLR9配体）处理的人肾细胞和小鼠中的作用。TIFA位于肾组织中莲四叶草凝集素（LTL）阳性肾细胞中，通过免疫荧光染色显示。HK-2细胞暴露于LPS和ODN会导致线粒体跨膜电位破坏。透射电子显微镜（TEM）结果显示，TIFA敲低组线粒体损伤得到改善。此外，TIFA敲低导致ODN处理后膜联蛋白V阳性和PI阴性细胞百分比降低。在LPS和ODN处理后将si-TIFA转入HK-2细胞时，NLRP3、半胱天冬酶-1和GSDMD蛋白也减少。TIFA激活增强了IL-1β和IL-18的表达。这些结果表明，TIFA通过激活线粒体损伤诱导细胞焦亡。我们的研究提供了脓毒症后肾细胞反应的详细转录组学描述。我们的研究表明，TIFA通过激活线粒体损伤参与细胞焦亡，可能是治疗脓毒症诱导的肾损伤的治疗靶点。
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