Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation
| Autor: | Salma Begum, Edward Laufer, David T. Breault, Juilee Rege, William E. Rainey, Matthew Taylor, Celso E. Gomez-Sanchez, Emily C. Frucci, Mark S. Ansorge, Matthew Ullenbruch |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aldosterone synthase medicine.medical_specialty medicine.drug_class Mice Transgenic Designer Drugs Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Primary aldosteronism Zona fasciculata Internal medicine Hyperaldosteronism medicine Animals Cytochrome P-450 CYP11B2 Clozapine Receptor Muscarinic M3 Aldosterone biology Chemistry Adrenal cortex General Medicine medicine.disease 030104 developmental biology medicine.anatomical_structure Endocrinology Zona glomerulosa Mineralocorticoid 030220 oncology & carcinogenesis Hypertension Adrenal Cortex biology.protein GTP-Binding Protein alpha Subunits Gq-G11 Female Zona Glomerulosa Signal Transduction Research Article |
| Zdroj: | Journal of Clinical Investigation. 130:83-93 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci127429 |
| Popis: | The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin–angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by AngII activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal-wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system. |
| Databáze: | OpenAIRE |
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