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Podocarpusflavone alleviated renal fibrosis in obstructive nephropathy by inhibiting Fyn/Stat3 signaling pathway

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Abstract

Tubulointerstitial fibrosis is a common pathological change in end-stage renal disease. However, limited treatment methods are developed, and unexplained potential mechanisms of renal diseases are urgent problems to be solved. In the present research, we first elucidated the role of podocarpusflavone (POD), a biflavone compound, in unilateral ureteral obstruction (UUO) in rodent model which is characterized by inflammation and fibrosis. The changes in histology and immunohistochemistry were observed that POD exerted renoprotective effects by retarding the infiltration of macrophage and aberrant deposition of ɑ-SMA, Col1a1, and fibronectin. Consistent with in vivo assay, POD treatment also ameliorated the process of fibrosis in TGF-β1-stimulated renal tubular epithelial cells and inflammation in LPS-induced RAW264.7 cells in vitro. In terms of mechanism, our results showed that treatment with POD inhibited the aggravated activation of Fyn in the UUO group, and weakened the level of phosphorylation of Stat3 which indicated that POD may alleviate the process of fibrosis by the Fyn/Stat3 signaling pathway. Furthermore, the gain of function assay by lentivirus-mediated exogenous forced expression of Fyn abrogated the therapeutic effect of the POD on renal fibrosis and inflammation. Collectively, it can be concluded that POD exerted a protective effect on renal fibrosis by mediating Fyn/Stat3 signaling pathway.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82104665); the Science and Technology Department of Sichuan Province (No. 2022YFS0621, No. 2023NSFSC1763); the Luzhou-Southwest Medical University Science and Technology Strategic Cooperation Project (No. 2021LZXNYD-P04, No. 2021LZXNYD-D13); the Funding Program of Southwest Medical University (No. 2021ZKZD022); the Innovation Team Project of Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University (No. 2022-CXTD-03).

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Author notes

  1. Bingwen Zhu and Rangyue Han contributed equally to this work.

Authors and Affiliations

  1. Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China

    Bingwen Zhu, Rangyue Han, Yufang Ni, Huaiying Guo, Xiaoheng Liu, Jianchun Li & Li Wang

  2. Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China

    Li Wang

  3. Southwest Medical University, Luzhou, 646000, Sichuan, China

    Bingwen Zhu & Rangyue Han

  4. The Clinical Laboratory of the Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China

    Huaiying Guo

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  1. Bingwen Zhu
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Contributions

BZ and JL substantially contributed to the conception and design of the study. BZ, RH, YN, HG and XL acquired, analyzed and interpreted the data. BZ drafted the article and critically revised it for important intellectual content. JL and LW agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

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Correspondence to Jianchun Li or Li Wang.

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Supplementary Information

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11418_2023_1685_MOESM1_ESM.tif

Supplementary file1 The molecular docking between POD and members of the Src family of kinases. A–E. The interaction between POD and Src (−4.2 kcal/mol) (A), Yes (−5.62 kcal/mol) (B), Lyn (−4.89 kcal/mol) (C), FGR (−4.41 kcal/mol) (D) and Lck (−5.35 kcal/mol) (E).(TIF 28380 KB)

11418_2023_1685_MOESM2_ESM.tif

Supplementary file2 Supplementary Fig. 2 POD reduced inflammation in vitro through a Fyn-dependent mechanism. A–D. The mRNA level of Fyn (A), IL-1β (B), IL-6 (C) and TNF-ɑ (D) in all groups of RAW264.7 cells. F (4, 25)=102.6, F (4, 25)=94.81, F (4, 25)=136.1, F (4, 25)=126.5. ***P < 0.001 vs. the Control group, ###P < 0.001 vs. the LPS group, @@@P < 0.001 vs. the LPS group, n.s. means no significant difference vs the LPS+Fyn-OE group. (TIF 6557 KB)

Supplementary file3 (PDF 19443 KB)

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Zhu, B., Han, R., Ni, Y. et al. Podocarpusflavone alleviated renal fibrosis in obstructive nephropathy by inhibiting Fyn/Stat3 signaling pathway. J Nat Med 77, 464–475 (2023). https://doi.org/10.1007/s11418-023-01685-y

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