全转录组图谱揭示 TFP5 治疗糖尿病肾病的 lncRNA 调控网络。
Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy.
机构信息
Department of Nephrology, Ningxia Medical University Affiliated People's Hospital of Autonomous Region, No. 301 Zhengyuan North Street, Yinchuan, 750001, People's Republic of China.
The Third Clinical Medical College, Ningxia Medical University, Yinchuan, People's Republic of China.
出版信息
Genes Genomics. 2024 May;46(5):621-635. doi: 10.1007/s13258-024-01504-y. Epub 2024 Mar 27.
BACKGROUND
TFP5 is a Cdk5 inhibitor peptide, which could restore insulin production. However, the role of TFP5 in diabetic nephropathy (DN) is still unclear.
OBJECTIVE
This study aims to characterize the transcriptome profiles of mRNA and lncRNA in TFP5-treated DN mice to mine key lncRNAs associated with TFP5 efficacy.
METHODS
We evaluated the role of TFP5 in DN pathology and performed RNA sequencing in C57BL/6J control mice, C57BL/6J db/db model mice, and TFP5 treatment C57BL/6J db/db model mice. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were analyzed. WGCNA was used to screen hub-gene of TFP5 in treatment of DN.
RESULTS
Our results showed that TFP5 therapy ameliorated renal tubular injury in DN mice. In addition, compared with the control group, the expression profile of lncRNAs in the model group was significantly disordered, while TFP5 alleviated the abnormal expression of lncRNAs. A total of 67 DElncRNAs shared among the three groups, 39 DElncRNAs showed a trend of increasing in the DN group and decreasing after TFP treatment, while the remaining 28 showed the opposite trend. DElncRNAs were enriched in glycosphingolipid biosynthesis signaling pathways, NF-κB signaling pathways, and complement activation signaling pathways. There were 1028 up-regulated and 1117 down-regulated DEmRNAs in the model group compared to control group, and 123 up-regulated and 153 down-regulated DEmRNAs in the TFP5 group compared to the model group. The DEmRNAs were involved in PPAR and MAPK signaling pathway. We confirmed that MSTRG.28304.1 is a key DElncRNA for TFP5 treatment of DN. TFP5 ameliorated DN maybe by inhibiting MSTRG.28304.1 through regulating the insulin resistance and PPAR signaling pathway. The qRT-PCR results confirmed the reliability of the sequencing data through verifying the expression of ENSMUST00000211209, MSTRG.31814.5, MSTRG.28304.1, and MSTRG.45642.14.
CONCLUSION
Overall, the present study provides novel insights into molecular mechanisms of TFP5 treatment in DN.
背景
TFP5 是一种 Cdk5 抑制剂肽，可恢复胰岛素的产生。然而，TFP5 在糖尿病肾病（DN）中的作用仍不清楚。
目的
本研究旨在描述 TFP5 治疗 DN 小鼠的 mRNA 和 lncRNA 转录组谱，以挖掘与 TFP5 疗效相关的关键 lncRNA。
方法
我们评估了 TFP5 在 DN 病理中的作用，并对 C57BL/6J 对照小鼠、C57BL/6J db/db 模型小鼠和 TFP5 治疗 C57BL/6J db/db 模型小鼠进行了 RNA 测序。分析差异表达的 lncRNA（DElncRNA）和 mRNA（DEmRNA）。使用 WGCNA 筛选 TFP5 治疗 DN 的关键基因。
结果
我们的结果表明，TFP5 治疗可改善 DN 小鼠的肾小管损伤。此外，与对照组相比，模型组的 lncRNA 表达谱明显紊乱，而 TFP5 可减轻 lncRNA 的异常表达。三组共有 67 个 DElncRNA，39 个 DElncRNA 在 DN 组呈上升趋势，TFP 治疗后下降，其余 28 个呈相反趋势。DElncRNA 富集在糖脂生物合成信号通路、NF-κB 信号通路和补体激活信号通路。与对照组相比，模型组有 1028 个上调和 1117 个下调的 DEmRNA，与模型组相比，TFP5 组有 123 个上调和 153 个下调的 DEmRNA。DEmRNA 参与 PPAR 和 MAPK 信号通路。我们证实 MSTRG.28304.1 是 TFP5 治疗 DN 的关键 DElncRNA。TFP5 通过抑制胰岛素抵抗和 PPAR 信号通路改善 DN。qRT-PCR 结果通过验证 ENSMUST00000211209、MSTRG.31814.5、MSTRG.28304.1 和 MSTRG.45642.14 的表达，证实了测序数据的可靠性。
结论
总之，本研究为 TFP5 治疗 DN 的分子机制提供了新的见解。
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