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

Authors
  • Hong, Weilong1
  • Zhang, Ge2
  • Lu, Hong3
  • Guo, Yangyang1
  • Zheng, Shizhang1
  • Zhu, Hengyue1
  • Xiao, Yanyi1
  • Papa, Akuetteh Percy David1
  • Wu, Cunzao4
  • Sun, Linxiao1
  • Chen, Bicheng1
  • Bai, Yongheng1, 5
  • 1 The First Affiliated Hospital of Wenzhou Medical University, Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Wenzhou, 325000, China , Wenzhou (China)
  • 2 People’s Hospital of Luzhou City, Department of Orthopedics, Luzhou, 646000, China , Luzhou (China)
  • 3 The First Affiliated Hospital of Wenzhou Medical University, Department of Laboratory Medicine, Wenzhou, 325000, China , Wenzhou (China)
  • 4 The First Affiliated Hospital of Wenzhou Medical University, Department of Transplantation, Wenzhou, 325000, China , Wenzhou (China)
  • 5 Wenzhou Medical University, Institute of Kidney Health, Center for Health Assessment, Wenzhou, 325000, China , Wenzhou (China)
Type
Published Article
Journal
Cell Communication and Signaling
Publisher
BioMed Central
Publication Date
Nov 12, 2019
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12964-019-0455-y
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundNotch1 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.MethodsThe 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-β1/Smad2/3 signalling was also investigated.ResultsNotch1 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 α-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-β1/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-β1, also induced epithelial and interstitial Notch1 activity, indicating that TGF-β1 may engage in crosstalk with Notch1 signalling to trigger fibrogenesis.ConclusionThese 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-β1/Smad2/3 signalling.

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