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Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy

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Abstract

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.

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Data availability

The datasets described here are accessible via NCBI accession numbers PRJNA924084.

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Acknowledgements

Not applicable.

Funding

This research was supported by National Natural Science Foundation of China (Nos. 81860136, 81460161), Natural Science Foundation of Ningxia Province (Nos. 2022AAC02059, NZ17186, 2021AAC03311), and The Key Research and Development Program of Ningxia Province Region projects (Nos. 2022BEG03121, 2018BFG0210).

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Author notes

  1. Hongyan Luo, Lirong Yang and Guoqing Zhang have contributed equally to this work.

Authors and Affiliations

  1. 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

    Hongyan Luo, Lirong Yang, Guoqing Zhang, Xi Bao, Danna Ma, Bo Li, Li Cao, Shilu Cao, Shunyao Liu, Li Bao, Jing E & Yali Zheng

  2. The Third Clinical Medical College, Ningxia Medical University, Yinchuan, People’s Republic of China

    Hongyan Luo, Xi Bao, Shilu Cao, Shunyao Liu, Li Bao & Yali Zheng

  3. Department of Nephrology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China

    Danna Ma & Jing E

  4. Department of Nephrology Hospital, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China

    Bo Li

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by LY, GZ, XB, DM, BL, LC, SC, SL, LB, JE. The first draft of the manuscript was written by HL, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yali Zheng.

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The study was approved by the Ningxia Medical University Affiliated People’s Hospital of Autonomous Region of Yinchuan.

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Supplementary Information

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13258_2024_1504_MOESM1_ESM.tif

Supplementary file 1. GO analysis of the target genes of DElncRNAs. (A) GO analysis of target genes of up-regulated DElncRNAs in model group compared with ctrl group. (B) GO analysis of target genes of down-regulated DElncRNAs in model group compared with ctrl group. (C) GO analysis of target genes of up-regulated DElncRNAs in TFP5 group compared with model group. (D) GO analysis of target genes of down-regulated DElncRNAs in TFP5 group compared with model group (TIF 1315 kb)

13258_2024_1504_MOESM2_ESM.tif

Supplementary file 2. The overlap KEGG signaling pathway analysis. Pathway node overlap indicates shared pathway genes. (A) The overlap KEGG signal pathway in the target of down-regulated DElncRNAs in model group compared with ctrl group and the target genes of up-regulated DElncRNAs in TFP5 group compared with model group. (B) The overlap KEGG pathway in the target of up-regulated DElncRNAs in model group compared to ctrl group and the target genes of down-regulated DElncRNAs in TFP5 group compared with model group (TIF 238 kb)

13258_2024_1504_MOESM3_ESM.tif

Supplementary file 3. GO analysis of the target genes of DEmRNAs. (A) GO analysis of up-regulated DEmRNAs in model group compared to ctrl group. (B) GO analysis of down-regulated DEmRNAs in model group compared to ctrl group. (C) GO analysis of up-regulated DEmRNAs in TFP5 group compared to model group. (D) GO analysis of down-regulated DEmRNAs in TFP5 group compared to model group (TIF 1524 kb)

13258_2024_1504_MOESM4_ESM.tif

Supplementary file 4. KEGG analysis of the target genes of DEmRNAs. (A) KEGG analysis of up-regulated DEmRNAs in model group compared with ctrl group. (B) KEGG analysis of down-regulated DEmRNAs in model group compared with ctrl group. (C) KEGG analysis of up-regulated DEmRNAs in TFP5 group compared with model group. (D) KEGG analysis of down-regulated DEmRNAs in TFP5 group compared with model group (TIF 1301 kb)

13258_2024_1504_MOESM5_ESM.tiff

Supplementary file 5. GCNA of all samples. (A) Clustering dendrogram of the sequencing data from 15 samples. (B) Determination of the soft threshold. (C) Clustering dendrogram for genes. Each color indicates one co-expression gene module. (D) Heatmap depicting correlations between module and samples (TIFF 1304 kb)

Supplementary file 6. The primer’s sequences used in this study (DOCX 13 kb)

Supplementary file 7. The detail expression, fold change, and p-values of common 67 DElncRNAs (XLSX 33 kb)

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Luo, H., Yang, L., Zhang, G. et al. Whole transcriptome mapping reveals the lncRNA regulatory network of TFP5 treatment in diabetic nephropathy. Genes Genom 46, 621–635 (2024). https://doi.org/10.1007/s13258-024-01504-y

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