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. 2016 Apr 5;7(14):17508-19.
doi: 10.18632/oncotarget.7919.

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

Hongrui Guo  1 , Hengmin Cui  1   2 , Xi Peng  1   2 , Jing Fang  1   2 , Zhicai Zuo  1   2 , Junliang Deng  1   2 , Xun Wang  1   2 , Bangyuan Wu  1 , Kejie Chen  1 , Jie Deng  1
Affiliations

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

Hongrui Guo et al. Oncotarget. .

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.

Keywords: ER stress; IRE1; Immune response; Immunity; Immunology and Microbiology Section; NiCl2; PERK; UPR.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Histopathological changes in the kidney at 42 days of age (HE)
a. Control group. No changes are observed; b. 300 mg/kg group. Tubular cells show granular and vacuolar degeneration. Few necrotic tubular cells and apoptotic tubular cells are also observed. c. 600 mg/kg group. Tubular cells show marked granular and vacuolar degeneration. Also, some necrotic tubular cells and apoptotic tubular cells are observed. d. 900 mg/kg group. A large number of necrotic tubular cells (▲) and apoptotic tubular cells (↑) are observed. e. Necrotic tubular cells (▲) and apoptotic tubular cells (↑) are observed.
Figure 2
Figure 2. Changes of GRP78 and GRP94 mRNA expression levels at 14, 28 and 42 days
Data are presented with the mean ± standard deviation (n = 5) *P < 0.05, compared with the control group; ** P < 0.01, compared with the control group.
Figure 3
Figure 3. Representative images of GRP78 protein expression by immunohistochemistry at 14, 28 and 42 days of age in the kidney
Figure 4
Figure 4. Representative images of GRP94 protein expression by immunohistochemistry at 14, 28 and 42 days of age in the kidney
Figure 5
Figure 5. Changes of GRP78 and GRP94 protein expression levels at 14, 28 and 42 days
Data are presented with the mean ± standard deviation (n = 5 × 5) *P < 0.05, compared with the control group; **P < 0.01, compared with the control group.
Figure 6
Figure 6. Changes of eIF2α and ATF4 mRNA expression levels at 14, 28 and 42 days
Data are presented with the mean ± standard deviation (n = 5) *P < 0.05, compared with the control group; **P < 0.01, compared with the control group.
Figure 7
Figure 7. Changes of IRE1 and XBP1 mRNA expression levels at 14, 28 and 42 days
Data are presented with the mean ± standard deviation (n = 5) *P < 0.05, compared with the control group; **P < 0.01, compared with the control group.
Figure 8
Figure 8. Changes of ATF6 mRNA expression levels at 14, 28 and 42 days
Data are presented with the mean ± standard deviation (n = 5) *P < 0.05, compared with the control group; **P < 0.01, compared with the control group.
Figure 9
Figure 9. Schematic diagram of NiCl2-caused ER stress
NiCl2 in excess of 300 mg/kg induces the ER stress. And PERK, IRE1 and ATF6 UPR pathways are all involved in NiCl2-induced ER stress.
See this image and copyright information in PMC

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