MicroRNA-183 exerts a protective role in lupus nephritis through blunting the activation of TGF-β/Smad/TLR3 pathway via reducing Tgfbr1
MicroRNA-183 exerts a protective role in lupus nephritis through blunting the activation of TGF-β/Smad/TLR3 pathway via reducing Tgfbr1
复制标题
DOI：
10.1016/j.yexcr.2020.112138
复制
发表时间：
2020-09-15
影响因子：
3.7
通讯作者：
Liu, Qiang
中科院分区：
文献类型：
--
作者：
Qi, Huimeng;Cao, Qin;Liu, Qiang
目的：microRNA（miR）-183在系统性红斑狼疮中的作用已被阐明，但其是否也参与狼疮性肾炎（LN）的发展仍不清楚。方法：在MRL/lpr小鼠模型中检测miR-183在8周和12周时的表达，并观察miR-183过表达或沉默对LN小鼠肾纤维化和炎症反应的影响。我们进一步在人肾小球内皮细胞（HRGECs）中过表达或敲低miR-183，并检测细胞中炎症因子、波形蛋白（Vimentin）和α-SMA的表达模式。利用生物信息学网站预测的miR-183的靶向mRNA，通过基因芯片技术筛选高表达miR-183的HRGECs中差异表达的基因。结果：miR-183在MRL/lpr小鼠中的表达明显降低，而miR-183的表达增加可抑制LN小鼠的肾纤维化和炎症反应。miR-183抑制剂可显著促进HRGECs中Vimentin和α-SMA的表达及炎性因子的分泌。结论：miR-183通过直接靶向阻断TGF-β/Smad/TLR 3通路，抑制Tgfbr 1的表达，从而抑制LN肾纤维化和炎症因子的分泌。
Purpose: The role of microRNA (miR)-183 has been elucidated in systemic lupus erythematosus, while whether it is also engaged in the lupus nephritis (LN) development remains opaque. The intention of this study is to examine the relevance of miR-183 downregulation in the pathogenesis of LN.Methods: The expression of miR-183 was first detected in MRL/lpr mice at weeks 8 and 12, followed by the assessment the effects of miR-183 on renal fibrosis and inflammatory response after overexpression or silencing of miR-183 in mice with LN. We further overexpressed or knocked-down miR-183 in human renal glomerular endothelial cells (HRGECs), and detected the expression patterns of inflammatory factors and Vimentin and alpha-SMA in the cells. Differentially expressed genes in HRGECs overexpressing miR-183 by microarrays were intersected with targeting mRNAs of miR-183 predicted by bioinformatics websites. The effects of transforming growth factor beta receptor 1 (Tgfbr1) and TGF-beta/Smad/TLR3 pathway on renal damage in mice were verified by rescue experiments.Results: miR-183 expression was notably lower in MRL/lpr mice, and increased miR-183 expression inhibited renal fibrosis and inflammatory response in mice with LN. Moreover, miR-183 inhibitor in HRGECs remarkably promoted the expression of Vimentin and alpha-SMA and the secretion of inflammatory factors. miR-183 protected the mouse kidney from pathological damages by targeting and inhibiting Tgfbr1 expression.Conclusion: miR-183 inhibited the expression of Tgfbr1 by direct targeting to disrupt the TGF-beta/Smad/TLR3 pathway, thus repressing renal fibrosis and the secretion of inflammatory factors in LN.