Int J Med Sci 2023; 20(12):1631-1643. doi:10.7150/ijms.79827 This issue Cite

Research Paper

DKK1 Ameliorates Myofibroblast Differentiation in Urethral Fibrosis in Vivo and in Vitro by Regulating the Canonical Wnt Pathway

Shanlong Huang1†, Delai Fu1†, Ziyan Wan1, Zhixin Huang1, Min Li2, Hecheng Li1, Tie Chong1✉

1. Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, China.
2. Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, China.
†These authors contributed equally to this work.

Citation:
Huang S, Fu D, Wan Z, Huang Z, Li M, Li H, Chong T. DKK1 Ameliorates Myofibroblast Differentiation in Urethral Fibrosis in Vivo and in Vitro by Regulating the Canonical Wnt Pathway. Int J Med Sci 2023; 20(12):1631-1643. doi:10.7150/ijms.79827. https://www.medsci.org/v20p1631.htm
Other styles

File import instruction

Abstract

Graphic abstract

Background: Urethral stricture is a common disorder of the lower urinary tract in men. A complex network of pathways and interactions are involved in the pathogenesis of urethral fibrosis. However, the mechanisms underlying urethral fibrosis remain poorly understood.

Objectives: To investigate the critical role of the canonical Wnt pathway in development of urethral fibrosis and explore DKK1, the endogenous inhibitor of Wnt pathway, as a potential target to prevent urethral fibrosis in vitro and in vivo.

Methods: Urethral fibrosis tissue derived from patients and rat models were harvested to assess the activation of the canonical Wnt pathway by using western blot, qRT-PCR and immunohistochemistryWe performed histological staining, western blot, qRT-PCR and immunohistochemistry to examine the effects of DKK1 treatment on in vivo rat urethral fibrosis models. In vitro, human urethral fibroblasts (HUFs) were cultured to examine the effects of DKK1 in TGFβ1-induced HUFs by CCK-8 assay, hydroxyproline assay, flow cytometry, cell migration assay, western blot, qRT-PCR and immunofluorescence.

Results: The key components of Wnt signaling were upregulated in urethral fibrosis tissue derived from patients and rat models while DKK 1 was downregulated. DKK1 ameliorated TGFβ1-induced urethral fibrosis in rats. TGFβ1 induced myofibroblast differentiation by upregulating collagen I, collagen III, α-SMA, β-catenin and p-GSK-3β, while DKK1 was decreased. DKK1 significantly inhibited cell proliferation, collagen content, cell migration and promoted cell apoptosis in TGFβ1-induced HUFs. DKK1 significantly suppressed myofibroblast differentiation of TGFβ1-induced HUFs by downregulating collagen I, collagen III, α-SMA, β-catenin and p-GSK-3β with a mechanism independent of Smad2/3.

Conclusions: Our study demonstrated that canonical Wnt pathway may be an essential mechanism underlying the pathogenesis of urethral fibrosis and explored the potential role of DKK1 participation in the development of urethral fibrosis.

Keywords: urethral stricture, urethral fibrosis, Wnt pathway, myofibroblast differentiation, DKK1


Citation styles

APA
Huang, S., Fu, D., Wan, Z., Huang, Z., Li, M., Li, H., Chong, T. (2023). DKK1 Ameliorates Myofibroblast Differentiation in Urethral Fibrosis in Vivo and in Vitro by Regulating the Canonical Wnt Pathway. International Journal of Medical Sciences, 20(12), 1631-1643. https://doi.org/10.7150/ijms.79827.

ACS
Huang, S.; Fu, D.; Wan, Z.; Huang, Z.; Li, M.; Li, H.; Chong, T. DKK1 Ameliorates Myofibroblast Differentiation in Urethral Fibrosis in Vivo and in Vitro by Regulating the Canonical Wnt Pathway. Int. J. Med. Sci. 2023, 20 (12), 1631-1643. DOI: 10.7150/ijms.79827.

NLM
Huang S, Fu D, Wan Z, Huang Z, Li M, Li H, Chong T. DKK1 Ameliorates Myofibroblast Differentiation in Urethral Fibrosis in Vivo and in Vitro by Regulating the Canonical Wnt Pathway. Int J Med Sci 2023; 20(12):1631-1643. doi:10.7150/ijms.79827. https://www.medsci.org/v20p1631.htm

CSE
Huang S, Fu D, Wan Z, Huang Z, Li M, Li H, Chong T. 2023. DKK1 Ameliorates Myofibroblast Differentiation in Urethral Fibrosis in Vivo and in Vitro by Regulating the Canonical Wnt Pathway. Int J Med Sci. 20(12):1631-1643.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image