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.

中文翻译：

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全转录组图谱揭示了 TFP5 治疗糖尿病肾病的 lncRNA 调控网络

背景

TFP5是一种Cdk5抑制肽，可以恢复胰岛素的产生。然而，TFP5在糖尿病肾病（DN）中的作用仍不清楚。

客观的

本研究旨在表征 TFP5 治疗的 DN 小鼠中 mRNA 和 lncRNA 的转录组谱，以挖掘与 TFP5 功效相关的关键 lncRNA。

方法

我们评估了 TFP5 在 DN 病理学中的作用，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 RNA 测序。分析了差异表达的lncRNA（DElncRNA）和mRNA（DEmRNA）。采用WGCNA筛选治疗DN的TFP5 hub基因。

结果

我们的结果表明，TFP5 疗法可改善 DN 小鼠的肾小管损伤。此外，与对照组相比，模型组lncRNA的表达谱明显紊乱，而TFP5则缓解了lncRNA的异常表达。三组共有 67 个 DElncRNA，其中 39 个 DElncRNA 在 DN 组中呈增加趋势，在 TFP 处理后呈减少趋势，而其余 28 个则呈相反趋势。 DElncRNA 富含鞘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个上调的DEmRNA和1117个下调的DEmRNA；与模型组相比，TFP5组有123个上调的DEmRNA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可能通过调节胰岛素抵抗和PPAR信号通路抑制MSTRG.28304.1来改善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

总体而言，本研究为 TFP5 治疗 DN 的分子机制提供了新的见解。