CircNr1h4 regulates the pathological process of renal injury in salt-sensitive hypertensive mice by targeting miR-155-5p
CircNr1h4 regulates the pathological process of renal injury in salt-sensitive hypertensive mice by targeting miR-155-5p
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DOI：
10.1111/jcmm.14863
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发表时间：
2019-11-28
影响因子：
5.3
通讯作者：
Weng, Huachun
中科院分区：
文献类型：
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作者：
Lu, Chaosheng;Chen, Bicheng;Weng, Huachun
环状RNA是一类广泛存在的内源性RNA，在多种疾病中可能调控基因表达，但其在高血压肾损伤中的调控和功能尚不清楚。在这项研究中，我们从正常小鼠肾脏和由脱氧皮质酮醋酸盐高血压诱导的损伤小鼠肾脏中产生了核糖体耗尽的RNA测序数据，并确定了至少4900个circRNA候选者。其中124个circRNA在正常和受损肾脏之间差异表达。此外，我们还鉴定了一种丰富的circRNA，称为circNr 1h 4，它来源于Nr 1h 4基因，并在损伤的肾脏中显著下调。RNA测序数据和qPCR分析还显示，许多microRNA和mRNA，包括miR-155- 5 p和脂肪酸还原酶1（Far 1），在正常和受损肾脏之间差异表达，并与circNr 1h 4相关。在体外，沉默circNr 1h 4或过表达miR-155- 5 p可显著降低Far 1水平并增加活性氧。机制研究表明，circNr 1h 4作为miR-155- 5 p的竞争性内源性RNA，导致其靶基因Far 1的调节。我们的研究为高血压肾损伤的分子机制提供了新的见解，这将是开发靶向circRNA治疗高血压肾损伤的治疗策略所必需的。
Circular RNAs are a class of widespread and diverse endogenous RNAs that may regulate gene expression in various diseases, but their regulation and function in hypertensive renal injury remain unclear. In this study, we generated ribosomal-depleted RNA sequencing data from normal mouse kidneys and from injured mouse kidneys induced by deoxycorticosterone acetate-salt hypertension and identified at least 4900 circRNA candidates. A total of 124 of these circRNAs were differentially expressed between the normal and injured kidneys. Furthermore, we characterized one abundant circRNA, termed circNr1h4, which is derived from the Nr1h4 gene and significantly down-regulated in the injured kidneys. RNA sequencing data and qPCR analysis also showed many microRNAs and mRNAs, including miR-155-5p and fatty acid reductase 1 (Far1), were differentially expressed between the normal and injured kidney and related to circNr1h4. In vitro, the silencing of circNr1h4 or overexpression of miR-155-5p significantly decreased Far1 levels and increased reactive oxygen species. Mechanistic investigations indicated that circNr1h4 acts as a competing endogenous RNA for miR-155-5p, leading to regulation of its target gene Far1. Our study provides novel insight into the molecular mechanisms underlying kidney injury in hypertension, which will be required to develop therapeutic strategies of targeting circRNAs for hypertensive kidney injury.