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Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia

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Abstract

Purpose

Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients.

Methods

Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation.

Results

Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway.

Conclusion

Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.

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Data availability

Derived data supporting the findings of this study are available from the corresponding author YN Niu on request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number:82000718 and 82170783) and Youth Talent Cultivation Program of Beijing (grant number: QML20230904).

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Author notes

  1. Song Jin and Zhanliang Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Beijing Tsinghua Changgung Hospital, Tsinghua University, No. 168, Litang Road, Beijing, 102218, China

    Song Jin, Meng Fu, Gang Zhang & Jianxing Li

  2. Department of Urology, Beijing Friendship Hospital, Capital Medical University, No. 95, Yongan Road, Beijing, 100050, China

    Song Jin, Zhanliang Liu & Yinong Niu

  3. Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China

    Peng Xiang

Authors
  1. Song Jin
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  2. Zhanliang Liu
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  3. Peng Xiang
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  4. Meng Fu
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  5. Gang Zhang
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  6. Jianxing Li
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  7. Yinong Niu
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Contributions

SJ: project development, manuscript writing; ZLL: project development, manuscript writing; XP: data collection; MF: project development; GZ: project development; JXL: manuscript writing and editing; YNN: project development, manuscript writing and editing.

Corresponding authors

Correspondence to Jianxing Li or Yinong Niu.

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Conflict of interests

The authors declare that they have no conflict of interest.

Ethical approval

Ethics Committee of Beijing Tsinghua Changgung Hospital approved this study (20062-0-01), and written informed consent was obtained from each participating patient.

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Informed consent was obtained from all the individuals participants included in this study.

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Jin, S., Liu, Z., Xiang, P. et al. Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia. World J Urol 42, 333 (2024). https://doi.org/10.1007/s00345-024-04956-9

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  • DOI: https://doi.org/10.1007/s00345-024-04956-9

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