Nrf2 protects stellate cells from Smad-dependent cell activation
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Authors
Prestigiacomo, Vincenzo
Author (Corporation)
Publication date
07/2018
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Type
01A - Journal article
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Parent work
PLOS ONE
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Volume
13
Issue / Number
7
Pages / Duration
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Publisher / Publishing institution
Public Library of Science
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Abstract
Hepatic stellate cells (HSC) orchestrate the deposition of extracellular matrix (ECM) and are the primary effector of liver fibrosis. Several factors, including TGF-β1, PDGF and oxidative stress, have been shown to trigger HSC activation. However, the involvement of cellular defence mechanisms, such as the activation of antioxidant response by Nrf2/Keap1 in the modulation of HSC activation is not known. The aim of this work was to elucidate the role of Nrf2 pathway in HSC trans-differentiation involved in the development of fibrosis. To this end, we repressed Nrf2 and Keap1 expression in HSC with specific siRNAs. We then assessed activation markers, as well as proliferation and migration, in both primary and immortalised human HSCs exposed to Smad inhibitors (SB-431542 hydrate and SB-525334), TGF-β1 and/or PDGF. Our results indicate that knocking down Nrf2 induces HSC activation, as shown by an increase in αSMA-positive cells and by gene expression induction of ECM components (collagens and fibronectin). HSC with reduced Nrf2-levels also showed an increase in migration and a decrease in proliferation. We could also demonstrate that the activation of Nrf2-deficient HSC involves the TGF-β1/Smad pathway, as the activation was successfully inhibited with the two tested Smad inhibitors. Moreover, TGF-β1 elicited a stronger induction of HSC activation markers in Nrf2 deficient cells than in wild type cells. Thus, our data suggest that Nrf2 limits HSCs activation, through the inhibition of the TGF-β1/Smad pathway in HSCs.
Keywords
TGF-β1, Nrf2, Hepatic stellate cells (HSC), extracellular matrix (ECM), Liver fibrosis
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ISBN
ISSN
1932-6203
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
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Peer review of the complete publication
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Citation
Prestigiacomo, V., & Suter-Dick, L. (2018). Nrf2 protects stellate cells from Smad-dependent cell activation. Plos One, 13(7). https://doi.org/10.1371/journal.pone.0201044