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Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland
bioRxiv - Molecular Biology Pub Date : 2020-10-15 , DOI: 10.1101/2020.10.15.340943
Deepika Watts , Nicole Bechmann , Ana Meneses , Ioanna K. Poutakidou , Denise Kaden , Catleen Conrad , Anja Krüger , Johanna Stein , Ali El-Armouche , Triantafyllos Chavakis , Graeme Eisenhofer , Mirko Peitzsch , Ben Wielockx

The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signalling on its function remains scarcely understood. Here, we reveal that deficiency of HIF (Hypoxia Inducible Factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Concomitant loss of PHD2 in renal erythropoietin (EPO) producing cells stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis) and systemic hypoglycaemia. Using mouse lines displaying only EPO-induced erythrocytosis or anaemia, we show that hypo- or hyperglycaemia is necessary and sufficient to respectively enhance or reduce exocytosis of epinephrine from the adrenal gland. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla and beyond regulates both synthesis and release of catecholamines, especially epinephrine. Our findings are also of great significance in view of the small molecule PHD inhibitors being tested in phase III global clinical development trials for use in renal anaemia patients.

中文翻译:

低氧途径蛋白调节小鼠肾上腺中肾上腺素的合成和释放

肾上腺及其激素调节许多基本的生物学过程。然而,对缺氧信号对其功能的影响了解甚少。在这里,我们揭示了小鼠肾上腺髓质中HIF(缺氧诱导因子)脯氨酰羟化酶域蛋白2(PHD2)的缺乏会导致HIF2α介导的苯乙醇胺N-甲基转移酶(PNMT)表达的减少,从而减少肾上腺素的合成。肾促红细胞生成素(EPO)产生细胞中PHD2的同时丧失会刺激HIF2α驱动的EPO过度产生,过多的RBC形成(红细胞增多)和系统性低血糖症。使用仅显示EPO引起的红细胞增多症或贫血的小鼠品系,我们表明低血糖或高血糖对于分别增强或减少肾上腺肾上腺素的胞吐作用是必要和充分的。根据这些结果,我们认为肾上腺髓质中的PHD2-HIF2α轴可调节儿茶酚胺尤其是肾上腺素的合成和释放。考虑到小分子PHD抑制剂正在肾贫血患者的III期全球临床开发试验中进行测试,我们的发现也具有重要意义。
更新日期:2020-10-17
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