Abstract
Background
Resveratrol (RSV) exerts anti-fibrotic effects on various fibrotic diseases. Whereas the biological role of RSV on urethral fibrosis remains to be elucidated. This study aimed to determine the mechanisms by which RSV affects urethral fibrosis and autophagy.
Methods
Sprague‒Dawley rats and primary fibroblasts were treated with transforming growth factor-β1 (TGFβ1) to generate in vivo and in vitro fibrosis models. Then, those were treated with RSV, and autophagy and fibrosis-related indicators were tested.
Results
Firstly, we found that RSV reversed the upregulation of indicators related to TGFβ1-induced fibrosis (TGFβ1, α-smooth muscle actin, collagen type I, and collagen type III), autophagy (TFEB and LC3), and TGFβR1/Smad4 pathway, as well as the downregulation of p62 and miR-192-5p expression both in vivo and in vitro. Overexpression of miR-192-5p suppressed the upregulation of fibrosis-related markers expression, as well as TFEB and LC3 expression, induced by TGFβ1, while the expression trend of p62 was the opposite. Inhibiting miR-192-5p reversed the effects of RSV on the model group cells. It was also shown that RSV combined with sh-Smad4 inhibited autophagy more effectively than RSV alone.
Conclusion
These results suggest that RSV inhibits urinary fibrosis and autophagy via the miR-192-5p/TGFβR1/Smad4 pathway. RAV may be a potential drug for alleviating urethral fibrosis.
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This work was supported by all authors. Design of the work and funding acquisition was performed by Yan Liu. Jin Lv, Rui Zhang and Daoyuan Li prepared the material and collected data. Funding acquisition was performed by DaoYuan Li. Jin Lv wrote the first draft of the manuscript. The data analysis was performed by Yan Liu, Jin Lv and Rui Zhang. All authors read and approved the final manuscript.
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Additional file 1: Figure S1.
Experimental design flowchart. RSV affects TGFβ1-induced autophagy and fibrosis via the miR-192-5p/TGFβR1/Smad4 pathway in vivo and in vitro.
Additional file 2: Figure S2.
Screening of TGFβ1 and RSV-treated cell conditions and the effect of autophagy inhibitor 3-MA on cell fibrosis. (A) The Vimentin level, a fibroblast marker, was measured by immunofluorescence (IF, 400×); scale bar, 25 μm. (B-C) Cells were treated with different concentrations of TGFβ1 for 24 and 48 h, and then cell viability and the expression of collagen I and III were assayed. (D) Cells were treated with TGFβ1(10 ng/mL) or TGFβ1(10 ng/mL) and 3-MA (1 mM) for 24 h, and the expressions of collagen I and III, as well as α-SMA, was detected by western blot. (E) Cells were treated with different concentrations of RSV for 24 h, and then cell viability was measured. (F) Cells were treated with TGFβ1(10 ng/mL) for 24 h, and the relative expressions of miR-192-5p, miR-146, and miR-21, was detected by western blot. (G) The expression levels of miR-192-5p, Tgfbr1 and Smad4 in urethral tissue were detected by qRT-PCR two weeks after injection of TGFβ1. *P < 0.05, ***P < 0.001 vs. the control group; ###P<0.001 vs. the model group.
Additional file 3: Figure S3.
MiR-192-5p may not target the 3’UTR of the Tgfbr1 gene. (A) Relative expression of Tgfbr1 in urethral fibroblasts was detected by qRT-PCR. (B) TGFβR1 expression in urethral fibroblasts was analyzed by western blot. (C) MiR-192-5p and Tgfbr1 binding site prediction. (D) Dual-luciferase reporter assay. **P < 0.001 vs. the NC mimic group; ###P<0.001 vs. the NC inhi group; ns means no significance.
Additional file 4: Figure S4.
The possibility of binding between RSV and protein molecules. (A) Hnf4α; (B) ETS1; (C) HNF1α; (D) SMAD3; (E) TWIST1.
Additional file 5: Figure S5.
RSV reverses TGFβ1-stimulated expression of Wnk1 and Atf1. Relative expression of Anapc10, Wnk1, Pdp1, Dbt, Atf1, Nefl, and Alcam in urethral fibroblasts was detected by qRT-PCR. ***P < 0.001 and **P<0.01 vs. the Control group; ##P < 0.01 and #P < 0.05 vs. the model group; ns means no significance.
Additional file 6:
Table S1. Antibodies for western blot. Table S2. Primer sequences were applied for qRT-PCR.
Additional file 7: Table S3.
Transcription factors associated with miR-192 were predicted.
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Lv, J., Zhang, R., Li, D. et al. Resveratrol plays an anti-fibrotic and anti-autophagy role by stimulating miR-192-5p expression in urethral fibrosis. Funct Integr Genomics 23, 241 (2023). https://doi.org/10.1007/s10142-023-01173-2
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DOI: https://doi.org/10.1007/s10142-023-01173-2