Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis

doi:10.1186/s12964-019-0455-y

科研成果详情

题名	Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis
作者	Hong, Weilong1; Zhang, Ge 2; Lu, Hong3; Guo, Yangyang1; Zheng, Shizhang 1; Zhu, Hengyue 1; Xiao, Yanyi 1; Papa, Akuetteh Percy David 1; Wu, Cunzao4; Sun, Linxiao1; Chen, Bicheng1; Bai, Yongheng1,5
发表日期	2019-11-12
发表期刊	CELL COMMUNICATION AND SIGNALING 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Notch1 signalling Myofibroblastic phenotype Epithelial-mesenchymal transition (EMT) Fibroblast-myofibroblast differentiation (FMD) Renal fibrosis
其他关键词	TO-MESENCHYMAL TRANSITION ; GAMMA-SECRETASE INHIBITOR ; CELL-CYCLE ARREST ; RENAL FIBROSIS ; SIGNALING PATHWAY ; MOLECULAR-MECHANISMS ; KIDNEY DEVELOPMENT ; ACTIVATION ; EXPRESSION ; ORIGIN
摘要	Background Notch1 signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis. However, the role of Notch1 in the formation of myofibroblasts and fibrosis in kidneys following injury remains unknown. Methods The activity of Notch1 signalling was evaluated in fibrotic kidneys in CKD patients and in ureteral obstructive models in vivo and in cultured fibroblasts and TECs in vitro. In addition, the crosstalk of Notch1 with TGF-beta 1/Smad2/3 signalling was also investigated. Results Notch1 activity was elevated in fibrotic kidneys of rat models and patients with chronic kidney disease (CKD). Further study revealed that epithelial and interstitial Notch1 activity correlated with an alpha-SMA-positive myofibroblastic phenotype. In vitro, injury stimulated epithelial Notch1 activation and epithelial-mesenchymal transition (EMT), resulting in matrix deposition in tubular epithelial cells (TECs). Additionally, interstitial Notch1 activation in association with fibroblast-myofibroblast differentiation (FMD) in fibroblasts mediated a myofibroblastic phenotype. These TGF-beta 1/Smad2/3-dependent phenotypic transitions were abolished by Notch1 knockdown or a specific antagonist, DAPT, and were exacerbated by Notch1 overexpression or an activator Jagged-1-Fc chimaera protein. Interestingly, as a major driving force behind the EMT and FMD, TGF-beta 1, also induced epithelial and interstitial Notch1 activity, indicating that TGF-beta 1 may engage in crosstalk with Notch1 signalling to trigger fibrogenesis. Conclusion These findings suggest that epithelial and interstitial Notch1 activation in kidneys following injury contributes to the myofibroblastic phenotype and fibrosis through the EMT in TECs and to the FMD in fibroblasts by targeting downstream TGF-beta 1/Smad2/3 signalling.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81772264, 81572087]; Natural Science Foundation of Zhejiang province, ChinaNatural Science Foundation of Zhejiang Province [LY17H050005, LQ16H310005, LY16H050007]; Science and Technology Plan Project of Sichuan province, China [2015JY0224]; Wenzhou Municipal Science and Technology Plan Project [Y20190124]
出版者	BMC
出版地	LONDON
ISSN	1478-811X
EISSN	1478-811X
卷号	17 期号:1 页码:145
DOI	10.1186/s12964-019-0455-y
页数	16
WOS类目	Cell Biology
WOS研究方向	Cell Biology
WOS记录号	WOS:000497680700001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	31718671
PMC记录号	PMC6849313
SCOPUSEID	2-s2.0-85074918874
通讯作者地址	[Chen, Bicheng]Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China ; [Bai, Yongheng]Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China
Scopus学科分类	Biochemistry;Molecular Biology;Cell Biology
引用统计	被引频次：11[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/15374
专题	第一临床医学院（信息与工程学院）、附属第一医院_浙江省胰脏肝脏危重性疾病重点实验室检验医学院（生命科学学院、生物学实验教学中心）附属第一医院_移植科
通讯作者	Chen, Bicheng; Bai, Yongheng
作者单位	1.Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China; 2.Department of Orthopedics,People's Hospital of Luzhou City,Luzhou,646000,China; 3.Department of Laboratory Medicine,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China; 4.Department of Transplantation,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,China; 5.Institute of Kidney Health,Center for Health Assessment,Wenzhou Medical University,Wenzhou,325000,China
第一作者单位	附属第一医院
通讯作者单位	附属第一医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Hong, Weilong,Zhang, Ge,Lu, Hong,et al. Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis[J]. CELL COMMUNICATION AND SIGNALING,2019,17(1):145.
APA	Hong, Weilong., Zhang, Ge., Lu, Hong., Guo, Yangyang., Zheng, Shizhang., ... & Bai, Yongheng. (2019). Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis. CELL COMMUNICATION AND SIGNALING, 17(1), 145.
MLA	Hong, Weilong,et al."Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis".CELL COMMUNICATION AND SIGNALING 17.1(2019):145.