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.
Highlights
Notch1 signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis
Epithelial and interstitial Notch1 signalling is activated in kidneys following injury First, we evaluated myofibroblastic phenotype and fibrosis in the obstructed kidneys
The levels of transforming growth factor-β1 (TGF-β1) and its receptor TGF-β1 receptor (TGF-β1R) were increased in the obstructive kidneys (Additional file 2: Figure S2A-C), which resulted in the activation of Smad2/3 downstream signalling
Summary
Notch signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis. Amelioration of EMT with the treatment of TGF-β1 signalling antagonists bone morphogenetic protein-7 (BMP-7) or Smad significantly alleviates fibrotic lesions [11, 12]. As a stem-cell-related signalling process, Notch signalling plays crucial roles in tissue regeneration, organogenesis and embryonic development [15, 16]. Overactivation of Notch signalling results in a series of pathological consequences, including different types of tumours [17, 18]. In addition to these effects, activated Notch signalling is reported to contribute to fibrosis in many tissues, including the kidney [19]. The underlying molecular mechanisms by which Notch signalling drives the fibrotic response have not been fully elucidated
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