Effects of a gamma‐secretase inhibitor of notch signalling on transforming growth factor β1‐induced urethral fibrosis. Issue 18 (6th August 2021)

• Record Type: Journal Article
• Authors: Huang, Shanlong; Fu, Delai; Wan, Ziyan; Li, Min; Li, Hecheng; Chong, Tie
• Is Part Of: Journal of cellular and molecular medicine. Volume 25:Issue 18(2021)
• Page Start: 8796
• Page End: 8808
• Publication Date: 2021-08-06
• Subjects: DAPT -- human urethral scar fibroblast -- Notch signalling -- transforming growth factor β1 -- urethral fibrosis -- urethral stricture; Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.16837
• Languages: English
• ISSNs: 1582-1838

Abstract

Abstract: Urethral stricture (US) is a common disorder of the lower urinary tract in men caused by fibrosis. The recurrence rate of US is high; however, there are no effective therapies to prevent or treat urethral fibrosis. The pathogenesis of urethral fibrosis involves myofibroblast activation and excessive extracellular matrix (ECM) deposition. The molecular mechanisms underlying this pathological activation are not completely understood. It has been demonstrated that Notch signalling contributes to the development of fibrosis and inflammation. However, whether this contributes to urethral fibrosis remains unclear. In this study, activation of Notch signalling was observed in patients with US. Additionally, it was noted that activation of Notch signalling promoted ECM production and myofibroblast activation in human urethral scar fibroblasts (HUSFs) treated with transforming growth factor (TGF) β1. However, the Notch inhibitor N ‐[ N ‐(3, 5‐difluorophenacetyl)‐L‐alanyl]‐S‐phenylglycine t‐butyl ester (DAPT) suppressed activation of Notch signalling as well as proliferation and migration of the TGFβ1‐treated HUSFs. Additionally, DAPT ameliorated TGFβ1‐induced urethral fibrosis in Sprague Dawley rats by suppressing ECM production, myofibroblast activation and the TGFβ signalling pathway. These findings demonstrate that Notch signalling may be a promising and potential target in the prevention or treatment of urethral fibrosis.