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首页> 外文期刊>EBioMedicine >H19 promote calcium oxalate nephrocalcinosis-induced renal tubular epithelial cell injury via a ceRNA pathway
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H19 promote calcium oxalate nephrocalcinosis-induced renal tubular epithelial cell injury via a ceRNA pathway

机译：H19通过ceRNA途径促进草酸钙肾钙化病引起的肾小管上皮细胞损伤

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Background Intrarenal calcium oxalate (CaOx) crystals induce inflammation and kidney tubular cell injury, which are processes that involve TLR4/NF-κB signalling. A recent genome-wide gene expression profile analysis of Randall's plaques in CaOx stone patients revealed that the expression of the long noncoding RNA H19 was significantly upregulated. However, to date, its role in kidney CaOx stones has not been reported. Method A Gene Expression Omnibus (GEO) dataset was utilized to analyse gene expression profiles. Luciferase reporter, Western blotting, qRT-PCR, immunofluorescence staining and reactive oxygen species (ROS) assays were employed to study the molecular mechanism of HMGB1/TLR4/NF-κB regulation by H19 and miR-216b. In vitro and in vivo assays were performed to further confirm the proinflammatory and prooxidative stress effects. Finding H19 expression was significantly increased and positively correlated with the expression levels of HMGB1, TLR4 and NF-κB in Randall's plaques and glyoxylate-induced CaOx nephrocalcinosis mouse models. H19 interacted with miR-216b and suppressed its expression. Additionally, miR-216b inhibited HMGB1 expression by directly binding its 3′-untranslated region. Moreover, H19 downregulation inhibited HMGB1, TLR4 and NF-κB expression and suppressed CaOx nephrocalcinosis-induced renal tubular epithelial cell injury, NADPH oxidase, and oxidative stress in vivo and in vitro . Interestingly, miR-216b inhibition partially reversed the inhibitory effect of H19 knockdown on HMGB1 expression. Interpretation We determined that H19 might serve as a facilitator in the process of CaOx nephrocalcinosis-induced oxidative stress and renal tubular epithelial cell injury, and?we revealed that the interaction between H19 and miR-216b could exert its effect via the HMGB1/TLR4/NF-κB pathway. Funding This work was supported by the National Nature Science Foundation of China (Nos. 8196030190 , 8190033175 , 81370805 , 81470935 , 81900645 , 81500534 , and 81602236 ).
机译：背景肾内草酸钙（CaOx）晶体会引起炎症和肾小管细胞损伤，这些过程涉及TLR4 /NF-κB信号传导。最近对CaOx结石患者的Randall斑块进行全基因组基因表达谱分析，结果表明长非编码RNA H19的表达明显上调。然而，迄今为止，尚未报道其在肾脏CaOx结石中的作用。方法利用基因表达综合（GEO）数据集分析基因表达谱。采用荧光素酶报告基因，Western印迹，qRT-PCR，免疫荧光染色和活性氧（ROS）分析研究了H19和miR-216b调控HMGB1 / TLR4 /NF-κB的分子机制。进行体外和体内测定以进一步确认促炎和促氧化应激作用。在兰德尔斑块和乙醛酸诱导的CaOx肾钙化病小鼠模型中，发现H19表达显着增加并与HMGB1，TLR4和NF-κB的表达水平正相关。 H19与miR-216b相互作用并抑制其表达。另外，miR-216b通过直接结合其3'-非翻译区来抑制HMGB1表达。此外，H19的下调抑制了HMGB1，TLR4和NF-κB的表达，并在体内外抑制了CaOx肾钙化病引起的肾小管上皮细胞损伤，NADPH氧化酶和氧化应激。有趣的是，miR-216b抑制部分逆转了H19敲低对HMGB1表达的抑制作用。解释我们确定H19可能在CaOx肾钙化病引起的氧化应激和肾小管上皮细胞损伤的过程中起促进作用，并且我们揭示了H19与miR-216b之间的相互作用可以通过HMGB1 / TLR4 / NF-κB途径。资助这项工作得到了中国国家自然科学基金的资助（第8196030190，8190033175，81370805，81470935，81900645，81500534和81602236）。

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