Paeonol reverses promoting effect of the HOTAIR/miR-124/Notch1 axis on renal interstitial fibrosis in a rat model
Paeonol reverses promoting effect of the HOTAIR/miR-124/Notch1 axis on renal interstitial fibrosis in a rat model
复制标题
丹皮酚逆转 HOTAIR/miR-124/Notch1 轴对大鼠模型肾间质纤维化的促进作用
DOI：
10.1002/jcp.28137
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发表时间：
2019-08-01
影响因子：
5.6
通讯作者：
Zheng, Jian
中科院分区：
文献类型：
--
作者：
Zhou, Hao;Qiu, Zhen-Zhen;Zheng, Jian
肾间质纤维化（RIF）是炎症性和非炎症性肾脏疾病的常见表现，与肾脏排泄功能障碍密切相关。近年来，长链非编码RNA（longnoncodingRNA，lncRNA）已被证实与多种肾脏疾病的发生发展有关。在这里，我们的目的是确定丹皮酚（PAE）是否影响RIF与lncRNA HOX转录反义基因间RNA（HOTAIR）/microRNA-124（miR-124）/Notch 1轴的参与。通过单侧输尿管闭塞（UUO）建立RIF大鼠模型，其中确定HOTAIR、Notch 1和miR-124之间的相互作用。为了确定PAE和HOTAIR在RIF中的作用，给大鼠注射HOTAIR或PAE。随后，为了进一步研究PAE在RIF中的潜在机制，测量了NRK-49 F细胞中的上皮向间质转化（EMT）和迁移相关基因。接下来，用IMR-1（Notch 1/Jagged 1信号通路抑制剂）进一步处理大鼠，以确定PAE如何影响Notch 1/Jagged 1信号通路。HOTAIR与miR-124相互作用，miR-124直接靶向Notch 1，在RIF大鼠中观察到HOTAIR上调。研究发现，PAE可降低RIF大鼠中HOTAIR和Notch 1的表达，但增加miR-124的表达。PAE抑制HOTAIR诱导的NRK-49 F细胞EMT和迁移。HOTAIR通过下调miR-124激活Notch 1/Jagged 1信号通路，而PAE逆转了HOTAIR对Notch 1/Jagged 1信号通路的这些作用。总体而言，我们的研究表明lncRNA HOTAIR通过抑制miR-124激活Notch 1/Jagged 1信号通路对RIF产生贡献作用，而给予PAE可减轻HOTAIR对RIF的影响。
Renal interstitial fibrosis (RIF) is a common manifestation of inflammatory and noninflammatory renal diseases, which correlates to renal excretory dysfunction. Recently, the long noncoding RNAs (lncRNAs) have been demonstrated to be involved in the development of various renal diseases. Here, we aim to determine whether paeonol (PAE) affects RIF with involvement of the lncRNA HOX transcript antisense intergenic RNA (HOTAIR)/microRNA-124 (miR-124)/Notch1 axis. RIF rat models were established by performing unilateral ureteral occlusion (UUO), in which interactions between HOTAIR, Notch1, and miR-124 were determined. To identify the roles of PAE and HOTAIR in RIF, rats were injected with HOTAIR or PAE. Subsequently, to further investigate the underlying mechanism of PAE in RIF, epithelial to mesenchymal transition (EMT)- and migration-related genes in NRK-49F cells were measured. Next, rats were further treated with IMR-1 (inhibitor of the Notch1/Jagged1 signaling pathway) to determine how PAE influences the Notch1/Jagged1 signaling pathway. HOTAIR interacted with miR-124, and miR-124 directly targeted Notch1, and HOTAIR was observed to be upregulated in RIF rats. PAE was found to decrease HOTAIR and Notch1 expression but to increase the miR-124 expression in RIF rats. PAE inhibited EMT and migration of NRK-49F cells facilitated by HOTAIR. HOTAIR activated the Notch1/Jagged1 signaling pathway by downregulating miR-124, while PAE reversed these effects of HOTAIR on the Notch1/Jagged1 signaling pathway. Overall, our study demonstrates the contributory effect of lncRNA HOTAIR on RIF by activating the Notch1/Jagged1 signaling pathway via inhibition of miR-124, whereas administration of PAE can alleviate the effects of HOTAIR on RIF.