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Chronic activation of adrenal Gq signaling induces Cyp11b2 expression in the zona fasciculata and hyperaldosteronism

  • 0Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Molecular and Cellular Endocrinology +

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February 10, 2024

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February 10, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Chronic Gq signaling disrupts adrenal aldosterone production by altering aldosterone synthase expression. This study used genetically modified mice to investigate the mechanisms behind this disruption.

Area Of Science

  • Endocrinology
  • Molecular Biology
  • Adrenal Gland Physiology

Background

  • Hyperaldosteronism involves inappropriate aldosterone production and CYP11B2 expression, typically confined to the adrenal zona glomerulosa (ZG).
  • Angiotensin II regulates CYP11B2 via Gq protein-coupled receptors, but the mechanism for ZG-specific expression remains unclear.
  • Adrenal cortex zonation involves differentiation into zona fasciculata (ZF) cells that normally lack CYP11B2.

Purpose Of The Study

  • To investigate the impact of chronic Gq signaling on adrenal aldosterone biosynthesis and CYP11B2 expression.
  • To determine if activating Gq signaling throughout the adrenal cortex disrupts normal zonal aldosterone production.
  • To explore the role of Gq signaling in the development of intra-adrenal renin-angiotensin-aldosterone system (RAAS).

Main Methods

  • Utilized transgenic mice expressing a clozapine N-oxide (CNO)-activated Gq-coupled human M3 muscarinic receptor (hM3Dq) throughout the adrenal cortex.
  • Administered CNO to activate the hM3Dq receptor and assessed circulating aldosterone levels under a high sodium diet.
  • Employed immunohistochemistry and transcriptomics to analyze CYP11B2 expression patterns and Wnt signaling.
  • Investigated the induction of an intra-adrenal RAAS in CNO-treated mice.

Main Results

  • Chronic Gq signaling activation (via CNO) increased circulating aldosterone, with a more pronounced effect in females.
  • Disrupted zonal CYP11B2 expression was observed, including expression in the ZF, indicating loss of ZG specificity.
  • Wnt signaling pathways remained unaffected by the chronic Gq activation.
  • An intra-adrenal RAAS was induced in mice treated with CNO.

Conclusions

  • Chronic Gq signaling disrupts the normal zonal regulation of aldosterone production in the adrenal cortex.
  • Aberrant CYP11B2 expression in the ZF is a key feature of Gq-mediated disruption of aldosterone biosynthesis.
  • These findings shed light on the mechanisms underlying hyperaldosteronism and potential therapeutic targets.

Keywords:

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