The Biomarker TCONS_00016233 Drives Septic AKI by Targeting the miR-22-3p/AIFM1 Signaling Axis
The Biomarker TCONS_00016233 Drives Septic AKI by Targeting the miR-22-3p/AIFM1 Signaling Axis
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TheBiomarkerTCONS_00016233通过靶向 miR-22-3p/AIFM1 信号轴驱动 SepticAKI
DOI：
10.1016/j.omtn.2019.12.037
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发表时间：
2020-03-06
影响因子：
8.8
通讯作者：
Zhang, Dongshan
中科院分区：
文献类型：
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作者：
Zhang, Pan;Yi, Lei;Zhang, Dongshan
败血症急性肾损伤（AKI）的死亡率的预测已通过许多潜在的生物标志物进行评估，包括长期非编码RNA（LNCRNA）。但是，仍然有必要确认LNCRNA作为生物标志物，尤其是在化粪池AM的早期阶段。我们的结果表明，LNCRNA TCONS_00016233在与败血症相关的非AKI和AKI患者的血浆中上调，但较高的截止阈值（9.5 x 10（5），拷贝数）提供了71.9％的敏感性为71.9％，并且特异性为89.6％。血浆TCONS_00016233与血清肌酐，组织抑制剂金属蛋白酶-2（TIMP-2），胰岛素样生长因子结合蛋白7（IGFBP7），interleuukin-1β（IL-1β），肿瘤坏死因子α（crp）（tnf-alappha and tnf-alacta）高度相关。 TCONS_00016233。脂多糖（LPS）通过TOLL-样受体4（TLR4）/p38丝分裂原激活的蛋白激酶（MAPK）信号途径在人肾小管上皮（HK-2）细胞中诱导LNCRNA TCONS_00016233的表达。此外，TCONS_00016233介导LPS诱导的HK-2细胞凋亡以及IL-1β和TNF-Alpha的表达。从机械上讲，TCONS_00016233充当竞争性内源RNA（CERNA），以防止microRNA（miR）-22-3p介导的凋亡诱导因子线粒体相关的下调1（AIFM1）。最后，TCONS_00016233的过表达能够通过靶向miR-22-3p/aifm1轴来加剧LPS和CECAL连接和穿刺（CLP）引起的化粪池AKI。综上所述，我们的数据表明TCONS_00016233可以作为化粪池AM的早期诊断标记，可能是化粪池AKI的新型治疗靶标。
The prediction of mortality for septic acute kidney injury (AKI) has been assessed by a number of potential biomarkers, including long noncoding RNAs (lncRNAs). However, the validation of lncRNAs as biomarkers, particularly for the early stages of septic AM, is still warranted. Our results indicate that the lncRNA TCONS_00016233 is upregulated in plasma of sepsis-associated non-AKI and AKI patients, but a higher cutoff threshold (9.5 x 10(5), copy number) provided a sensitivity of 71.9% and specificity of 89.6% for the detection of AKI. The plasma TCONS_00016233 was highly correlated with serum creatinine, tissue inhibitor metalloproteinase-2 (TIMP-2), insulin-like growth factor binding protein-7 (IGFBP7), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), and urinary TCONS_00016233. Lipopolysaccharide (LPS) induced the expression of lncRNA TCONS_00016233 via the Toll-like receptor 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) signal pathway in human renal tubular epithelial (HK-2) cells. Furthermore, TCONS_00016233 mediates the LPS-induced HK-2 cell apoptosis and the expression of IL-1 beta and TNF-alpha. Mechanistically, TCONS_00016233 acts as a competing endogenous RNA (ceRNA) to prevent microRNA (miR)-22-3p-mediated downregulation of the apoptosisinducing factor mitochondrion-associated 1 (AIFM1). Finally, overexpression of TCONS_00016233 is capable of aggravating the LPS- and cecal ligation and puncture (CLP)-induced septic AKI by targeting the miR-22-3p/AIFM1 axis. Taken together, our data indicate that TCONS_00016233 may serve as an early diagnosis marker for the septic AM, possibly acting as a novel therapeutic target for septic AKI.