Abstract
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.
Highlights
Glucocorticoids are the main effector hormones of the hypothalamic-pituitary-adrenal (HPA) axis and their levels dynamically increase with exposure to physiological and psychological stressors
We showed that stress modulates local mediators of glucocorticoid antioxidant responses in the liver
We showed that stress modulates local mediators of glucocorticoid bioavailability, including corticosteroid-binding globulin (CBG) and 11β-HSDs, reduces cellular antioxidant defense capacity likely via bioavailability, including CBG and 11β-HSDs, reduces cellular antioxidant defense capacity likely via suppression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated GSH production, and induces an overall hepatic oxidative and nitrosative suppression of Nrf2-mediated GSH production, and induces an overall hepatic oxidative and stress
Summary
Glucocorticoids (cortisol and corticosterone) are the main effector hormones of the hypothalamic-pituitary-adrenal (HPA) axis and their levels dynamically increase with exposure to physiological and psychological stressors. Termination of the stress response is mediated by glucocorticoids via negative feedback to the anterior pituitary, hypothalamus, and extra-hypothalamic. According to the free hormone hypothesis, this feedback is mediated by the unbound, physiologically active glucocorticoids that are able to cross the blood-brain barrier and bind glucocorticoid receptors [3]. Previous reports demonstrated that CBG, produced primarily in the liver, plays an important role in regulation of the stress response, with reductions in CBG expression transiently increasing free glucocorticoid bioavailability [6,7,8,9]. The action of glucocorticoids on target tissues is mediated by glucocorticoid (GR)
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