HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla.
Adrenal Medulla
/ metabolism
Animals
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Calcium
/ metabolism
Epinephrine
/ metabolism
Erythropoietin
/ metabolism
Female
Hypoglycemia
/ metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases
/ genetics
Male
Mice, Transgenic
Phenylethanolamine N-Methyltransferase
/ genetics
Polycythemia
/ metabolism
Tumor Cells, Cultured
Catecholamines
Glucose
Hypoxia inducible factor
Oxygen sensors
Journal
Journal of molecular medicine (Berlin, Germany)
ISSN: 1432-1440
Titre abrégé: J Mol Med (Berl)
Pays: Germany
ID NLM: 9504370
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
05
02
2021
accepted:
20
07
2021
revised:
16
07
2021
pubmed:
5
9
2021
medline:
25
2
2022
entrez:
4
9
2021
Statut:
ppublish
Résumé
The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly 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. Simultaneous loss of PHD2 in renal erythropoietin (EPO)-producing cells (REPCs) stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis), and systemic hypoglycemia, which is necessary and sufficient to enhance exocytosis of epinephrine from the adrenal medulla. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla regulates the synthesis of epinephrine, whereas in REPCs, it indirectly induces the release of this hormone. Our findings are also highly relevant to the testing of small molecule PHD inhibitors in phase III clinical trials for patients with renal anemia. KEY MESSAGES: HIF2α and not HIF1α modulates PNMT during epinephrine synthesis in chromaffin cells. The PHD2-HIF2α-EPO axis induces erythrocytosis and hypoglycemia. Reduced systemic glucose facilitates exocytosis of epinephrine from adrenal gland.
Identifiants
pubmed: 34480587
doi: 10.1007/s00109-021-02121-y
pii: 10.1007/s00109-021-02121-y
pmc: PMC8542008
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Epo protein, mouse
0
Erythropoietin
11096-26-7
endothelial PAS domain-containing protein 1
1B37H0967P
Egln1 protein, mouse
EC 1.14.11.29
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Phenylethanolamine N-Methyltransferase
EC 2.1.1.28
Calcium
SY7Q814VUP
Epinephrine
YKH834O4BH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1655-1666Informations de copyright
© 2021. The Author(s).
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