Abstract
In the last decades in vitro studies highlighted the potential for crosstalk between Hypoxia-Inducible Factor-(HIF) and glucocorticoid-(GC) signalling pathways. However, how this interplay precisely occurs in vivo is still debated. Here, we use zebrafish larvae (Danio rerio) to elucidate how and to what degree hypoxic signalling affects the endogenous glucocorticoid pathway and vice versa, in vivo. Firstly, our results demonstrate that in the presence of upregulated HIF signalling, both glucocorticoid receptor (Gr) responsiveness and endogenous cortisol levels are repressed in 5 days post fertilisation larvae. In addition, despite HIF activity being low at normoxia, our data show that it already impedes both glucocorticoid activity and levels. Secondly, we further analysed the in vivo contribution of glucocorticoids to HIF activity. Interestingly, our results show that both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) play a key role in enhancing it. Finally, we found indications that glucocorticoids promote HIF signalling via multiple routes. Cumulatively, our findings allowed us to suggest a model for how this crosstalk occurs in vivo.
Highlights
Glucocorticoids (GC) constitute a well-characterized class of lipophilic steroid hormones produced by the adrenal glands in humans and by the interrenal tissue in teleosts
Our results demonstrate that both glucocorticoid receptor (Gr) and mineralocorticoid receptor (Mr) loss of function are able to partially rescue vhl phenotype, allowing us to confirm the importance of glucocorticoids in assuring high Hypoxia-inducible factor (HIF) signalling levels
To study the interplay between HIF and GC signalling in vivo, using a genetic approach, we required a Hif1β/Arnt1 mutant line to enable the downregulation of the HIF pathway
Summary
Glucocorticoids (GC) constitute a well-characterized class of lipophilic steroid hormones produced by the adrenal glands in humans and by the interrenal tissue in teleosts. The circadian production of glucocorticoids in teleosts is regulated by the hypothalamus-pituitary-interrenal (HPI) axis, which is the equivalent of the mammalian hypothalamus-pituitary-adrenal (HPA) axis. Both are central to stress adaptation [1,2,3,4]. Both in humans and teleosts cortisol is the primary glucocorticoid and regulates a plethora of physiological processes including glucose homeostasis, inflammation, intermediary metabolism and stress response [5]. Cortisol can exert these functions via direct binding both to the glucocorticoid receptor (Gr) and to the mineralocorticoid receptor (Mr), which bind cortisol with different affinities. Together they act as a transcription factor, which can function either in a genomic or in non-genomic way [5,7,8,9]
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