tiRNA-Gly-GCC-002 通过 FKBP5 介导的 Smad 激活促进狼疮性肾炎的上皮-间质转化和纤维化。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Xueting Liu, Ji Zhang, Yan Liang, Xuanwen Chen, Shungang Xu, Sishi Lin, Yuanting Dai, Xinxin Chen, Ying Zhou, Yongheng Bai, Chaosheng Chen
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引用次数: 0

摘要

背景和目的:肾间质纤维化是狼疮性肾炎(LN)的一种常见病理表现。tRNA半核酸(tiRNAs)是从tRNA衍生的小非编码RNA(sncRNAs)中获得的,与纤维化有关。我们之前的研究表明,肾脏中 tiRNA-Gly-GCC-002(tiRNA002)水平的升高与 LN 相关纤维化呈正相关。然而,确切的分子机制仍不清楚:实验方法:通过转染将tiRNA002的模拟物和agomiR引入肾小管上皮细胞(TECs)和MRL/lpr小鼠。采用实时定量聚合酶链反应(RT-qPCR)、Western 印迹和免疫荧光检测法对基因和蛋白质的表达水平进行量化:主要结果:在用LN血清处理的TEC以及MRL/lpr小鼠的肾脏中,高水平的tiRNA002直接影响上皮-间质转化(EMT)和细胞外基质(ECM)沉积。此外,tiRNA002 的过表达促进了 TEC 的 EMT,并通过 Smad 信号加速了 MRL/lpr 小鼠肾间质纤维化。tiRNA002的靶基因FKBP脯氨酰异构酶5(FKBP5)通过与磷酸化的Smad2/3相互作用改善了Smad信号传导。沉默FKBP5可减轻LN血清或tiRNA002模拟物诱导的TECs EMT。此外,FKBP5的过表达逆转了tiRNA002敲除介导的EMT和ECM积累的减少:这些研究结果表明,tiRNA002 在 LN 中明显增加,它通过 FKBP5 介导的 Smad 信号促进 EMT,从而促进肾纤维化。因此,靶向 tiRNA002 可能是治疗 LN 肾间质纤维化的一种创新方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
tiRNA-Gly-GCC-002 promotes epithelial-mesenchymal transition and fibrosis in lupus nephritis via FKBP5-mediated activation of Smad.

Background and purpose: Renal interstitial fibrosis is a frequent pathological manifestation of lupus nephritis (LN). tRNA halves (tiRNAs) are acquired from tRNA-derived small non-coding RNAs (sncRNAs) and are associated with fibrosis. Our previous study indicated enhanced tiRNA-Gly-GCC-002 (tiRNA002) levels in kidneys were positively related to LN-related fibrosis. However, the precise molecular mechanism remains unclear.

Experimental approach: The mimic and agomiR of tiRNA002 were introduced into tubular epithelial cells (TECs) and MRL/lpr mice by transfection. The levels of gene and protein expressions were quantified using real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assays.

Key results: In TECs treated with LN serum, as well as in the kidneys of MRL/lpr mice, high levels of tiRNA002 directly influenced the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Furthermore, tiRNA002 overexpression promoted EMT in TECs and accelerated renal interstitial fibrosis in MRL/lpr mice via Smad signalling. The target gene of tiRNA002, FKBP prolyl isomerase 5 (FKBP5), improved Smad signalling by interacting with phosphorylated Smad2/3. Silencing FKBP5 alleviated LN serum- or tiRNA002-mimic-induced EMT in TECs. In addition, FKBP5 overexpression reversed the tiRNA002 knockdown-mediated reduction of EMT and ECM accumulation.

Conclusions and implications: These findings indicated that tiRNA002 is markedly increased in LN, which facilitates renal fibrosis by promoting EMT via FKBP5-mediated Smad signalling. Therefore, targeting tiRNA002 may be an innovative approach to treat renal interstitial fibrosis in LN.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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