Differentially expressed miRNAs in sepsis-induced acute kidney injury target oxidative stress and mitochondrial dysfunction pathways.
Differentially expressed miRNAs in sepsis-induced acute kidney injury target oxidative stress and mitochondrial dysfunction pathways.
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DOI：
10.1371/journal.pone.0173292
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Pan SM
中科院分区：
文献类型：
--
作者：
Ge QM;Huang CM;Zhu XY;Bian F;Pan SM
鉴定脓毒症诱导阿基的特异性miRNAs并探索其靶向通路。通过微阵列分析和定量PCR（qPCR）验证脓毒症诱导的阿基患者（n = 6）、脓毒症非阿基患者（n = 6）和健康志愿者（n = 3）的血清中的miRNA表达谱。采用Target Scan、mirbase和米兰达预测差异表达的miRNAs的靶点。然后分析了基因本体（GO）和KEGG信号通路的重要功能和参与信号通路的情况。此外，从差异表达的miRNA中随机选择8个miRNA用于通过qPCR进一步测试。qPCR分析证实，与健康志愿者相比，脓毒症患者hsa-miR-23 a-3 p、hsa-miR-4456、hsa-miR-142- 5 p、hsa-miR-22- 3 p和hsa-miR-191- 5 p的表达水平显著降低，而hsa-miR-4270、hsa-miR-4321、hsa-miR-3165在脓毒症患者中的表达水平显著升高。统计学上，与脓毒症-非阿基相比，脓毒症-诱导的阿基中miR-4321; miR-4270显著上调，而与对照组相比，脓毒症组中仅miR-4321显著过表达。GO分析表明，由预测的靶基因调控的生物学过程包括多种术语。它们与肾脏发育、氮化合物代谢过程的调控、细胞代谢过程的调控、细胞对氧化应激的反应、线粒体外膜透化等有关。通路分析表明，预测的靶基因中有几条重要通路与氧化应激有关。miR-4321参与调节AKT 1、mTOR和NOX 5的表达，而miR-4270参与调节PPARGC 1A、AKT 3、NOX 5、PIK 3C 3、WNT 1的表达。功能和途径分析强调了miRNA失调的mRNA可能参与氧化应激和线粒体功能障碍。本研究有助于加深对血清miRNAs与脓毒症阿基关系的认识，为进一步阐明脓毒症阿基与氧化应激和线粒体功能障碍的可能机制奠定重要基础。
To identify specific miRNAs involved in sepsis-induced AKI and to explore their targeting pathways. The expression profiles of miRNAs in serum from patients with sepsis-induced AKI (n = 6), sepsis-non AKI (n = 6), and healthy volunteers (n = 3) were investigated by microarray assay and validated by quantitative PCR (qPCR). The targets of the differentially expressed miRNAs were predicted by Target Scan, mirbase and Miranda. Then the significant functions and involvement in signaling pathways of gene ontology (GO) and KEGG pathways were analyzed. Furthermore, eight miRNAs were randomly selected out of the differentially expressed miRNAs for further testing by qPCR. qPCR analysis confirmed that the expressions levels of hsa-miR-23a-3p, hsa-miR-4456, hsa-miR-142-5p, hsa-miR-22-3p and hsa-miR-191-5p were significantly lower in patients with sepsis compared with the healthy volunteers, while hsa-miR-4270, hsa-miR-4321, hsa-miR-3165 were higher in the sepsis patients. Statistically, miR-4321; miR-4270 were significantly upregulated in the sepsis-induced AKI compared with sepsis-non AKI, while only miR-4321 significantly overexpressed in the sepsis groups compared with control groups. GO analysis showed that biological processes regulated by the predicted target genes included diverse terms. They were related to kidney development, regulation of nitrogen compound metabolic process, regulation of cellular metabolic process, cellular response to oxidative stress, mitochondrial outer membrane permeabilization, etc. Pathway analysis showed that several significant pathways of the predicted target genes related to oxidative stress. miR-4321 was involved in regulating AKT1, mTOR and NOX5 expression while miR-4270 was involved in regulating PPARGC1A, AKT3, NOX5, PIK3C3, WNT1 expression. Function and pathway analysis highlighted the possible involvement of miRNA-deregulated mRNAs in oxidative stress and mitochondrial dysfunction. This study might help to improve understanding of the relationship between serum miRNAs and sepsis-induced AKI, and laid an important foundation for further identification of the potential mechanisms of sepsis-induced AKI and oxidative stress and mitochondrial dysfunction.