Nickel oxide nanoparticles induce hepatocyte apoptosis via activating endoplasmic reticulum stress pathways in rats

Abstract

Nickel oxide nanoparticles (nano NiO) could induce hepatocyte apoptosis, while its potential mechanisms are unclear. This study aimed to explore the role of endoplasmic reticulum (ER) stress pathways in hepatocyte apoptosis induced by nano NiO. Male Wistar rats were administrated with nano NiO (0.015, 0.06, and 0.24 mg/kg b.w.) and micro NiO (0.24 mg/kg b.w.) by intratracheal instillation twice a week for 6 weeks. We measured the hepatocyte apoptosis levels by TdT-mediated dUTP nick-end labeling (TUNEL) staining, ER stress related gene and protein expression levels in rat liver. The results showed that the TUNEL positive cells increased after exposure nano NiO, hinting hepatocyte apoptosis. The up-regulated gene and protein levels of 78 kD glucose regulated protein and CCAAT/enhancer binding protein homologous protein suggested that nano NiO triggered ER stress. Nano NiO exposure contributed to the increased protein contents of inositol-requiring enzyme 1 (IRE-1)α, p-IRE-1α, X box protein-1S, pancreatic ER kinase (PERK), p-PERK, eukaryotic initiation factor-2 alpha (eIF-2α), p-eIF-2α, caspase-12, -9, and -3, implicating that nano NiO can activate the pathways of ER stress-mediated apoptosis. These findings indicate that the ER stress pathways may play an important role in hepatocyte apoptosis induced by nano NiO.

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

“…Nano NiO causes cytotoxicity via excessive ROS generation, and induces cell apoptosis mediated by bax/bcl‐2 pathway in HepG2 cells . Our previous studies found that Nano NiO evoked hepatocyte apoptosis via endoplasmic reticulum stress pathway in rats . Additionally, Nano NiO exerts hepatic toxicity through oxidative stress and NF‐κB signaling pathway .…”

“…In addition, chronic liver damage promotes hepatic fibrosis in animal models . Our previous studies found that Nano NiO induced sub‐chronic liver lesion, which was associated with oxidative stress, hepatocyte apoptosis, and activation of Nuclear factor‐kappa B (NF‐κB) signaling pathway . Based on the above studies, we hypothesized that Nano NiO could lead to hepatic fibrosis.…”

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

“…To quantify the relative mRNA expression of ERK1/2, P38 MAPK, MMP‐2, MMP‐9, TIMP‐1, and TIMP‐2, we performed RT‐qPCR with Bestar SYBR Green qPCR Mastermix kits (DBI Bioscience, Germany) in an IQ5 Multicolor Real‐Time PCR Detection System (Bio‐Rad, Hercules, California) according to the manufacturer's instructions. The steps of the program were described by our previous study . Beta‐actin (β‐actin) was used as the internal reference and we used the 2 −ΔΔct relative quantitation formula to quantify mRNA expression levels .…”

“…The steps of the program were described by our previous study. 1 Beta-actin (β-actin) was used as the internal reference and we used the 2 −ΔΔct relative quantitation formula to quantify mRNA expression levels. 31 The sequences and primers of all genes were designed and synthesized by Takara Biotechnology Co., Ltd. (Shanghai, China) and listed in Table 1.…”

“…Due to the unique physicochemical properties of Nickel oxide nanoparticles (Nano NiO), such as small size, large surface area, and high surface reactivity, it has been applied for medical healthcare, scientific research and other various industries. 1 Nevertheless, broad applications of Nano NiO increased the human exposure through various way especially via respiratory tract, resulting in pulmonary inflammation and pulmonary fibrosis, in which pulmonary fibrosis is the main symptom. [2][3][4] Our previous study found that Nano NiO induced lung fibrosis, and it could be related with transforming growth factor-β1 (TGF-β1) in rats.…”