Reverse Effect of Mammalian Hypocalcemic Cortisol in Fish: Cortisol Stimulates Ca2+ Uptake via Glucocorticoid Receptor-Mediated Vitamin D3 Metabolism

Cortisol was reported to downregulate body-fluid Ca 2+ levels in mammals but was proposed to show hypercalcemic effects in teleostean fish. Fish, unlike terrestrial vertebrates, obtain Ca 2+ from the environment mainly via the gills and skin rather than by dietary means, and have to regulate the Ca 2+ uptake functions to cope with fluctuating Ca 2+ levels in aquatic environments. Cortisol was previously found to regulate Ca 2+ uptake in fish; however, the molecular mechanism behind this is largely unclear. Zebrafish were used as a model to explore this issue. Acclimation to low-Ca 2+ fresh water stimulated Ca 2+ influx and expression of epithelial calcium channel ( ecac ), 11β-hydroxylase and the glucocorticoid receptor ( gr ). Exogenous cortisol increased Ca 2+ influx and the expressions of ecac and hydroxysteroid 11-beta dehydrogenase 2 (hsd11b2) , but downregulated 11β-hydroxylase and the gr with no effects on other Ca 2+ transporters or the mineralocorticoid receptor ( mr ). Morpholino knockdown of the GR, but not the MR, was found to impair zebrafish Ca 2+ uptake function by inhibiting the ecac expression. To further explore the regulatory mechanism of cortisol in Ca 2+ uptake, the involvement of vitamin D 3 was analyzed. Cortisol stimulated expressions of vitamin D-25hydroxylase ( cyp27a1 ), cyp27a1 like ( cyp27a1l ), 1α-OHase ( cyp27b1 ) at 3 dpf through GR, the first time to demonstrate the relationship between cortisol and vitamin D 3 in fish. In conclusion, cortisol stimulates ecac expression to enhance Ca 2+ uptake functions, and this control pathway is suggested to be mediated by the GR. Lastly, cortisol also could mediate vitamin D 3 signaling to stimulate Ca 2+ uptake in zebrafish.