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Article

Restraint Stress Alters Expression of Glucocorticoid Bioavailability Mediators, Suppresses Nrf2, and Promotes Oxidative Stress in Liver Tissue

1
School of Biomedical Sciences, The University of Queensland, St Lucia 4072, Australia
2
WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
3
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia
*
Authors to whom correspondence should be addressed.
Antioxidants 2020, 9(9), 853; https://doi.org/10.3390/antiox9090853
Received: 15 July 2020 / Revised: 8 September 2020 / Accepted: 9 September 2020 / Published: 11 September 2020
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
Hepatic glutathione synthesis and antioxidant protection are critically important for efficient detoxification processes in response to metabolic challenges. However, this biosynthetic pathway, regulated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), previously demonstrated paradoxical repression following exposure to glucocorticoid stress hormones in cultured hepatic cells. Therefore, the present study used an in vivo model of sub-acute psychological stress to investigate the relationship between hepatic corticosteroid regulation and antioxidant systems. Male Wistar rats were kept under control conditions or subjected to six hours of restraint stress applied for 1 or 3 days (n = 8 per group) after which the liver was isolated for assays of oxidative/nitrosative status and expression of corticosteroid regulatory and Nrf2-antioxidant response element pathway members. A single stress exposure produced a significant increase in the expression of corticosterone reactivator, 11-beta-hydroxysteroid dehydrogenase 1 (11β-Hsd1), while the 11β-Hsd2 isozyme and corticosteroid-binding globulin were down-regulated following stress, indicative of an elevated availability of active corticosterone. Exposure to restraint significantly decreased hepatic concentrations of total cysteine thiols and the antioxidant reduced glutathione on Day 1 and increased 3-nitrotyrosinated and carbonylated proteins on Day 3, suggestive of oxidative/nitrosative stress in the liver following stress exposure. Conversely, there was a sustained down-regulation of Nrf2 mRNA and protein in addition to significant reductions in downstream glutamate-cysteine ligase catalytic subunit (Gclc), the rate-limiting enzyme in glutathione synthesis, on Day 1 and 3 of stress treatment. Interestingly, other antioxidant genes including superoxide dismutase 1 and 2, and glutathione peroxidase 4 were significantly up-regulated following an episode of restraint stress. In conclusion, the results of the present study indicate that increased expression of 11β-Hsd1, indicative of elevated tissue glucocorticoid concentrations, may impair the Nrf2-dependent antioxidant response. View Full-Text
Keywords: antioxidant response; corticosteroids; liver; Nrf2; oxidative stress antioxidant response; corticosteroids; liver; Nrf2; oxidative stress
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MDPI and ACS Style

Chen, H.-J.C.; Yip, T.; Lee, J.K.; Juliani, J.; Sernia, C.; Hill, A.F.; Lavidis, N.A.; Spiers, J.G. Restraint Stress Alters Expression of Glucocorticoid Bioavailability Mediators, Suppresses Nrf2, and Promotes Oxidative Stress in Liver Tissue. Antioxidants 2020, 9, 853. https://doi.org/10.3390/antiox9090853

AMA Style

Chen H-JC, Yip T, Lee JK, Juliani J, Sernia C, Hill AF, Lavidis NA, Spiers JG. Restraint Stress Alters Expression of Glucocorticoid Bioavailability Mediators, Suppresses Nrf2, and Promotes Oxidative Stress in Liver Tissue. Antioxidants. 2020; 9(9):853. https://doi.org/10.3390/antiox9090853

Chicago/Turabian Style

Chen, Hsiao-Jou C., Tsz Yip, Johnny K. Lee, Juliani Juliani, Conrad Sernia, Andrew F. Hill, Nickolas A. Lavidis, and Jereme G. Spiers 2020. "Restraint Stress Alters Expression of Glucocorticoid Bioavailability Mediators, Suppresses Nrf2, and Promotes Oxidative Stress in Liver Tissue" Antioxidants 9, no. 9: 853. https://doi.org/10.3390/antiox9090853

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