TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Abstract

Nickel oxide nanoparticles (Nano NiO) bears hepatotoxicity, while whether it leads to liver fibrosis remains unclear. The aim of this study was to establish the Nano NiO‐induced hepatic fibrosis model in vivo and investigate the roles of transforming growth factor β1 (TGF‐β1) in Smad pathway activation, epithelial‐mesenchymal transition (EMT) occurrence, and extracellular matrix (ECM) deposition in vitro. Male Wistar rats were exposed to 0.015, 0.06, and 0.24 mg/kg Nano NiO by intratracheal instilling twice a week for 9 weeks. HepG2 cells were treated with 100 μg/mL Nano NiO and TGF‐β1 inhibitor (SB431542) to explore the mechanism of collagen formation. Results of Masson staining as well as the elevated levels of type I collagen (Col‐I) and Col‐III suggested that Nano NiO resulted in hepatic fibrosis in rats. Furthermore, Nano NiO increased the protein expression of TGF‐β1, p‐Smad2, p‐Smad3, alpha‐smooth muscle actin (α‐SMA), matrix metalloproteinase9 (MMP9), and tissue inhibitors of metalloproteinase1 (TIMP1), while decreased the protein content of E‐cadherin and Smad7 in rat liver and HepG2 cells. Most importantly, Nano NiO‐triggered the abnormal expression of the abovementioned proteins were all alleviated by co‐treatment with SB431542, implying that TGF‐β1‐mediated Smad pathway, EMT and MMP9/TIMP1 imbalance were involved in overproduction of collagen in HepG2 cells. In conclusion, these findings indicated that Nano NiO induced hepatic fibrosis via TGF‐β1‐mediated Smad pathway activation, EMT occurrence, and ECM deposition.

<p>Emodin Retarded Renal Fibrosis Through Regulating HGF and TGFβ–Smad Signaling Pathway</p>

“…These data are similar to a recent report, suggesting that HGF and/or emodin exhibit antifibrotic effects via suppression of the EMT process. TGFβ 1 signaling has been confirmed to be involved in fibrosis, 37,38 and is activated persistently in fibrosis. 39,40 Smad4 is at the core of the TGFβ 1 -signaling pathway.…”

All Roads Lead to the Liver: Metal Nanoparticles and Their Implications for Liver Health

“…[47] Nickel nanoparticles (44 nm) instilled intratracheally in Wistar rats led to increased staining for collagen-I in treated rats, showing that long-term exposure to nickel NPs was induced fibrosis. [48] Chen et al also found that mice injected intraperitoneally with titanium dioxide NPs (100 nm) developed hepatic fibrosis around the central vein, corresponding with areas of titanium dioxide NP attachment. [49] Exposure to silicon dioxide NPs (70 nm) twice a week for four weeks induced higher levels of the liver fibrosis marker hydroxyproline accompanying an increase in hepatic collagen staining in mice.…”

“…We note however that NPs can damage DNA, as well as provoke or worsen liver disorders such as liver fibrosis and steatosis. [48,49,109,113,114,121] Given that HCC is the terminal state for many liver disorders, [122] sufficiently long exposure periods coupled with a high dosage can presumably promote HCC development. As most NP hepatotoxicity studies rarely last longer than one year (Table 2), it may be that our current experimental models of exposing rodents to NPs are simply not being performed long enough for HCC to develop.…”

Assessing risks caused by nickel-based nanomaterials: hazardous factor identification

“…Data in the work [39] indicate that NiO NPs may produce fibrogenic effects on liver cells; it was shown that HEPG2 cells exposure to these NPs in a concentration equal to 100 µg/ml resulted in elevated expression of TGF-β1, p-Smad2, p-Smad3, -actin-smooth muscles, matrix metalloproteinase (MMP) of isoform 9, tissue inhibitor of metalloproteinase (TIMP)-1 and reduced E-cadherin and Smad7.…”