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Nrf2 deficiency aggravates the kidney injury induced by subacute cadmium exposure in mice

  • Inorganic Compounds
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Abstract

Cadmium (Cd) is a heavy metal pollutant that adversely effects the kidney. Oxidative stress and inflammation are likely major mechanisms of Cd-induced kidney injury. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is crucial in regulating antioxidant and inflammatory responses. To investigate the role of Nrf2 in the development of subacute Cd-induced renal injury, we utilized Nrf2 knockout (Nrf2-KO) and control mice (Nrf2-WT) which were given cadmium chloride (CdCl2, 1 or 2 mg/kg i.p.) once daily for 7 days. While subacute CdCl2 exposure induced kidney injury in a dose-dependent manner, after the higher Cd dosage exposure, Nrf2-KO mice showed elevated blood urea nitrogen (BUN) and urinary neutrophil gelatinase-associated lipocalin (NGAL) levels compared to control. In line with the findings, the renal tubule injury caused by 2 mg Cd/kg, but not lower dosage, in Nrf2-KO mice determined by Periodic acid–Schiff staining was more serious than that in control mice. Further mechanistic studies showed that Nrf2-KO mice had more apoptotic cells and severe oxidative stress and inflammation in the renal tubules in response to Cd exposures. Although there were no significant differences in Cd contents of tissues between Cd-exposed Nrf2-WT and Nrf2-KO mice, the mRNA expression of Nrf2 downstream genes, including heme oxygenase 1 and metallothionein 1, were significantly less induced by Cd exposures in the kidney of Nrf2-KO compared with Nrf2-WT mice. In conclusion, Nrf2-deficient mice are more sensitive to kidney injury induced by subacute Cd exposure due to a muted antioxidant response, as well as a likely diminished production of specific Cd detoxification metallothioneins.

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Abbreviations

AREs:

Antioxidant response elements

BUN:

Blood urea nitrogen

Cd:

Cadmium

CdCl2 :

Cadmium chloride

Cd–MTs:

Cd–metallothioneins

Cd68:

Cluster of differentiation 68

GSH:

Glutathione

Gclc:

Glutamate cysteine ligase catalytic subunit

Gclm:

Glutamate cysteine ligase modifier subunit

4-HNE:

4-Hydroxynonenal

Ho1:

Heme oxygenase 1

ICP-MS:

Inductively coupled plasma mass spectrometry

IL-6:

Interleukin-6

IHC:

Immunohistochemistry

KEAP1:

Kelch-like ECH-associated protein-1

MT:

Metallothionein

Nrf2:

Nuclear factor erythroid-derived 2-like 2

MRE:

Metal response elements

Nrf2-KO:

Nrf2 Knockout

Nrf2-WT:

Nrf2 Wild-type

NaCl:

Sodium chloride

NGAL:

Neutrophil gelatinase-associated lipocalin

Nqo1:

Nicotinamide adenine dinucleotide (phosphate):quinine oxidoreductase 1

PAS:

Periodic acid–Schiff

ROS:

Reactive oxygen species

SCR:

Serum creatinine

TNF:

Tumor necrosis factor

TUNEL:

TdT-mediated dUTP nick-end labeling

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Funding

This work was supported by National Natural Science Foundation of China 82020108027 (J.P.), 81830099 (J.P.), 81573106 (J.P.), 81770698 (H.Z) and 81402635 (J.F.), Liaoning Key Research and Development Guidance Plan 2019JH8/10300012 (J.P.), Liaoning Province Natural Science Foundation (20180530011, J.F.), Educational Department of Liaoning Province Scientific Research Foundation (ZF2019035, J.F.), China Medical University Training Program for National Natural Science Fund for Excellent Young Scholars (YQ20170001, J.F.), and the Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic. We thank Dr. Michael P. Waalkes for editorial support.

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Authors and Affiliations

  1. Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People’s Republic of China

    Chengjie Chen, Xue Han, Dan Liu, Lina Bao, Yongyong Hou, Jingqi Fu & Jingbo Pi

  2. Experimental and Teaching Center, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People’s Republic of China

    Gang Wang

  3. Department of Nephrology, The Affiliated Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People’s Republic of China

    Congcong Jiao, Junjun Luan & Hua Zhou

  4. Key Laboratory of Liaoning Province On Toxic and Biological Effects of Arsenic, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People’s Republic of China

    Yuanyuan Xu & Jingbo Pi

  5. Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People’s Republic of China

    Yuanyuan Xu & Huihui Wang

  6. Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA

    Qiang Zhang

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  1. Chengjie Chen
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  2. Xue Han
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  3. Gang Wang
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  9. Yuanyuan Xu
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  10. Huihui Wang
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  12. Hua Zhou
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  14. Jingbo Pi
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Correspondence to Jingqi Fu or Jingbo Pi.

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Chen, C., Han, X., Wang, G. et al. Nrf2 deficiency aggravates the kidney injury induced by subacute cadmium exposure in mice. Arch Toxicol 95, 883–893 (2021). https://doi.org/10.1007/s00204-020-02964-3

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