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. 2018 Jul 20;13(7):e0201044. doi: 10.1371/journal.pone.0201044

Fig 7. Nrf2 intervention into the TGF-β1/Smad signalling pathway.

Fig 7

Panel A, basal condition: HSCs express high levels of both Nrf2 and its target genes (e.g. Nqo1), thereby controlling reactive oxygen species (ROS) level. Nrf2 also inhibits Smad pathway by binding directly to Smad protein or through the action of phosphatases [41]. In these conditions, the TGF-β1/Smad pathway has a low activity, resulting in low level of αSMA, collagens and TGF-β1. Thus, HSC cells exhibit a quiescent phenotype. Panel B, Nrf2 knockdown: we have found out that Nrf2 knockdown, with a consequent decrease of its target genes, induces stellate cells activation. Decrease in Nrf2 was in fact associated with an increase in the levels of Extracellular matrix (ECM) components as well as αSMA and TGF-β1. TGF-β1 further induces the expression of ATF3, which acts as functional repressor of Nrf2. We found out that this siNrf2-induced stellate cell activation may be regulated by the Smad inhibitors SB-431542 hydrate (SB43) and SB-525334 (SB52), confirming the role of Nrf2 in relation to the Smad pathway.