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.
Highlights
Hepatic fibrosis is a scarring process in response to chronic liver injury, and it is characterized by an accumulation of fibrillar extracellular matrix (ECM) [1]
In primary Hepatic stellate cells (HSC), transforming growth factor-β1 (TGF-β1) significantly decreased the mRNA levels of both nuclear factor E2-related factor 2 (Nrf2) and Nqo1after 48 hours of exposure, but no change in expression was observed for Kelch-like ECH-associated protein 1 (Keap1) (Fig 1B)
Nrf2 has been identified as an important factor in HSC activation [3], the mechanism through which it acts in HSC remains unclear
Summary
Hepatic fibrosis is a scarring process in response to chronic liver injury, and it is characterized by an accumulation of fibrillar extracellular matrix (ECM) [1]. Hepatic stellate cells (HSCs) undergo activation, a cellular process during which HSCs transdifferentiate into myofibroblasts-like cells [1]. Activated HSC have been recognized as the responsible cells for most of the excess of ECM components in chronic liver fibrosis [1]. HSC activation is triggered by several cytokines; in particular platelet-derived growth factor (PDGF) and transforming growth factor-β1 (TGF-β1), released from platelet and Kupffer cells respectively, have been identified as the main mitogenic and pro-fibrotic mediators for HSCs [1].
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