Nickel chloride (NiCl2) induces endoplasmic reticulum (ER) stress by activating UPR pathways in the kidney of broiler chickens.

Hongrui Guo,Kejie Chen,Junliang Deng,Jie Deng,Xun Wang,Xi Peng,Zhicai Zuo,Hengmin Cui,Jing Fang,Bangyuan Wu

doi:10.18632/oncotarget.7919

Abstract

It has been known that overexposure to Ni can induce nephrotoxicity. However, the mechanisms of underlying Ni nephrotoxicity are still elusive, and also Ni- and Ni compound-induced ER stress has been not reported in vivo at present. Our aim was to use broiler chickens as animal model to test whether the ER stress was induced and UPR was activated by NiCl2 in the kidney using histopathology, immunohistochemistry and qRT-PCR. Two hundred and eighty one-day-old broiler chickens were divided into 4 groups and fed on a control diet and the same basal diet supplemented with 300 mg/kg, 600mg/kg and 900mg/kg of NiCl2 for 42 days. We found that dietary NiCl2 in excess of 300 mg/kg induced ER stress, which was characterized by increasing protein and mRNA expression of ER stress markers, e.g., GRP78 and GRP94. Concurrently, all the three UPR pathways were activated by dietary NiCl2. Firstly, the PERK pathway was activated by increasing eIF2a and ATF4 mRNA expression. Secondly, the IRE1 pathway was activated duo to increase in IRE1 and XBP1 mRNA expression. And thirdly, the increase of ATF6 mRNA expression suggested that ATF6 pathway was activated. The findings clearly demonstrate that NiCl2 induces the ER stress through activating PERK, IRE1 and ATF6 UPR pathways, which is proved to be a kind of molecular mechanism of Ni- or/and Ni compound-induced nephrotoxicity.

Highlights

Ni is ubiquitously in our environment, and exists various forms of Ni compounds in soil, water, air and living organisms [1]
We found that dietary NiCl2 in excess of 300 mg/kg induced ER stress, which was characterized by increasing protein and mRNA expression of ER stress markers, e.g., GRP78 and GRP94
The findings clearly demonstrate that NiCl2 induces the ER stress through activating PERK, IRE1 and ATF6 UPR pathways, which is proved to be a kind of molecular mechanism of Ni- or/and Ni compound-induced nephrotoxicity

Summary

Introduction

Ni is ubiquitously in our environment, and exists various forms of Ni compounds in soil, water, air and living organisms [1]. Ni is an ubiquitous transition metal that is industrially applied in many forms, which inevitably leads to a high degree of occupational and environmental exposure [2] This widespread extraction and use increase Ni concentrations in biogeochemical cycles and enhance human exposure to Ni and Ni compounds through environmental contamination and occupational exposure. Our studies have shown that dietary NiCl2 in 300 mg/kg and over can cause histopathological lesions, immunotoxicity, oxidative damage, apoptosis and cell cycle arrest in the kidney, thymus, spleen, small intestine, cecal tonsil and bursa of Fabricius of broiler chickens [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. NiONPs induce human bronchial epithelial cell toxicity through increasing SIRT1-mediated apoptosis [32].

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