The Bateson Centre & Department of Biomedical Science, Firth Court, University of Sheffield, Western Bank, Sheffield, United Kingdom.
Department of Genetic Engineering, SRM Institute of Science and Technology Kattankulathur, India.
PLoS Genet. 2020 May 7;16(5):e1008757. doi: 10.1371/journal.pgen.1008757. eCollection 2020 May.
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.
在过去的几十年中，体外研究强调了缺氧诱导因子（HIF）和糖皮质激素（GC）信号通路之间相互作用的潜力。然而，这种相互作用在体内是如何精确发生的，仍存在争议。在这里，我们使用斑马鱼幼虫（Danio rerio）来阐明体内缺氧信号是如何以及在何种程度上影响内源性糖皮质激素途径，反之亦然。首先，我们的结果表明，在 HIF 信号转导上调的情况下，5 天受精后幼虫的糖皮质激素受体（Gr）反应性和内源性皮质醇水平均受到抑制。此外，尽管在常氧条件下 HIF 活性较低，但我们的数据表明，它已经阻碍了糖皮质激素的活性和水平。其次，我们进一步分析了糖皮质激素对 HIF 活性的体内贡献。有趣的是，我们的结果表明，糖皮质激素受体（GR）和盐皮质激素受体（MR）都在增强 HIF 活性方面发挥了关键作用。最后，我们发现了糖皮质激素通过多种途径促进 HIF 信号转导的迹象。总之，我们的研究结果使我们能够提出一个关于这种体内相互作用发生的模型。
