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Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation
Matthew J. Taylor, … , David T. Breault, William E. Rainey
Matthew J. Taylor, … , David T. Breault, William E. Rainey
Published November 18, 2019
Citation Information: J Clin Invest. 2020;130(1):83-93. https://doi.org/10.1172/JCI127429.
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Research Article Endocrinology

Chemogenetic activation of adrenocortical Gq signaling causes hyperaldosteronism and disrupts functional zonation

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Abstract

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.

Authors

Matthew J. Taylor, Matthew R. Ullenbruch, Emily C. Frucci, Juilee Rege, Mark S. Ansorge, Celso E. Gomez-Sanchez, Salma Begum, Edward Laufer, David T. Breault, William E. Rainey

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Figure 3

AS+/Cre hM3Dq mice have increased expression of the ZG marker Dab2, with no changes in the ZG-specific Wnt pathway.

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AS+/Cre hM3Dq mice have increased expression of the ZG marker Dab2, wit...
(A) Immunofluorescence staining for the ZG-specific Dab2 protein (green). (B) qPCR analysis for whole adrenal Dab2 mRNA. (C) Immunofluorescence staining for active β-catenin (green). (D) qPCR analysis for whole adrenal mRNA expression of the Wnt pathway target gene Axin2. n = 8 for both CNO- and vehicle-treated groups in B and D. DAPI (blue) stained the nuclei in A and C. Scale bars: 50 μm. Data in the dot plots represent the mean ± SEM. *P < 0.05, by unpaired, 2-tailed Student’s t test.

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