Abstract
Stress, the physiological reaction to a stressor, is initiated in teleost fish by hormone cascades along the hypothalamus-pituitary-interrenal (HPI) axis. Cortisol is the major stress hormone and contributes to the appropriate stress response by regulating gene expression after binding to the glucocorticoid receptor. Cortisol is inactivated when 11β-hydroxysteroid dehydrogenase (HSD) type 2 catalyzes its oxidation to cortisone. In zebrafish, Danio rerio, cortisone can be further reduced to 20β-hydroxycortisone. This reaction is catalyzed by 20β-HSD type 2, recently discovered by us. Here, we substantiate the hypothesis that 20β-HSD type 2 is involved in cortisol catabolism and stress response. We found that hsd11b2 and hsd20b2 transcripts were up-regulated upon cortisol treatment. Moreover, a cortisol-independent, short-term physical stressor led to the up-regulation of hsd11b2 and hsd20b2 along with several HPI axis genes. The morpholino-induced knock down of hsd20b2 in zebrafish embryos revealed no developmental phenotype under normal culture conditions, but prominent effects were observed after a cortisol challenge. Reporter gene experiments demonstrated that 20β-hydroxycortisone was not a physiological ligand for the zebrafish glucocorticoid or mineralocorticoid receptor but was excreted into the fish holding water. Our experiments show that 20β-HSD type 2, together with 11β-HSD type 2, represents a short pathway in zebrafish to rapidly inactivate and excrete cortisol. Therefore, 20β-HSD type 2 is an important enzyme in stress response.
Highlights
Stress is an ancient evolutionary system that enables fast reflexive actions to cope with environmental stressors or dangerous situations, e.g., predators
As we attempted to elucidate the mechanism of 20b-hydroxysteroid dehydrogenase (HSD) type 2 action, we challenged the zebrafish embryos with cortisol concentrations that were significantly higher than physiological levels
We identified the novel enzyme 20b-HSD type 2 and hypothesized that the enzyme plays a role in cortisol catabolism in concert with 11b-HSD type 2 [36]
Summary
Stress is an ancient evolutionary system that enables fast reflexive actions to cope with environmental stressors or dangerous situations, e.g., predators. The first hormone secreted by the hypothalamus is corticotropin releasing hormone (CRH), which stimulates the corticotropic and melanotropic cells of the pituitary [3] to cleave the large proopiomelanocortin protein (POMC) [4] This cleavage allows adrenocorticotropic hormone (ACTH) to be secreted into the circulation and to bind the melanocortin 2 receptor (MC2R) on the surface of the interrenal cells in teleost fish [5]. Upon this stimulus, the interrenal cells enclosed in the head kidney synthesize and release cortisol into the circulation [6]. Afterwards, 17alpha-hydroxylation (Cyp17), 3b-hydroxysteroid dehydrogenation (Hsd3b), and 21-hydroxylation (Cyp21a1) occur prior to the last step in cortisol biosynthesis, which is 11-hydroxylation mediated by 11-hydroxylase (Cyp11c1) [7]
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