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Effects of a gamma-secretase inhibitor of notch signalling on transforming growth factor β1-induced urethral fibrosis
Journal of Cellular and Molecular Medicine ( IF 4.3 ) Pub Date : 2021-08-06 , DOI: 10.1111/jcmm.16837
Shanlong Huang 1 , Delai Fu 1 , Ziyan Wan 1 , Min Li 2 , Hecheng Li 1 , Tie Chong 1
Affiliation  

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.

中文翻译:

Notch信号转导的γ-分泌酶抑制剂对转化生长因子β1诱导的尿道纤维化的影响

尿道狭窄 (US) 是由纤维化引起的男性下尿路常见疾病。US复发率高;然而,没有有效的疗法来预防或治疗尿道纤维化。尿道纤维化的发病机制涉及肌成纤维细胞活化和过度的细胞外基质 (ECM) 沉积。这种病理激活的分子机制尚不完全清楚。已经证明,Notch 信号传导有助于纤维化和炎症的发展。然而,这是否会导致尿道纤维化仍不清楚。在这项研究中,在 US 患者中观察到 Notch 信号的激活。此外,值得注意的是,Notch 信号的激活促进了用转化生长因子 (TGF) β1 处理的人尿道瘢痕成纤维细胞 (HUSF) 中 ECM 的产生和肌成纤维细胞的活化。然而,Notch 抑制剂N -[ N -(3,5-二氟苯乙酰)-L-丙氨酰]-S-苯基甘氨酸叔丁酯 (DAPT) 抑制 Notch 信号的激活以及 TGFβ1 处理的 HUSF 的增殖和迁移。此外,DAPT 通过抑制 ECM 产生、肌成纤维细胞活化和 TGFβ 信号通路改善了 TGFβ1 诱导的 Sprague Dawley 大鼠尿道纤维化。这些发现表明,Notch 信号传导可能是预防或治疗尿道纤维化的有希望的潜在靶点。
更新日期:2021-09-13
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