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Calcineurin regulates aldosterone production via dephosphorylation of NFATc4


Berber, Mesut; Leng, Sining; Wengi, Agnieszka; Winter, Denise V; Odermatt, Alex; Beuschlein, Felix; Loffing, Johannes; Breault, David T; Penton, David (2023). Calcineurin regulates aldosterone production via dephosphorylation of NFATc4. Journal of clinical investigation insight, 8(14):e157027.

Abstract

The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (Calcineurin (Cn)) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium (K+)-stimulated expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomic analysis identified Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4) as a target for Cn-mediated dephosphorylation. Deletion of NFATc4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATc4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATc4 directly regulates CYP11B2 expression. Thus, calcineurin controls aldosterone production via the Cn-NFATc4 pathway. Inhibition of Cn-NFATc4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus and the Cn-NFATc4 pathway may provide novel molecular targets to treat primary aldosteronism.

Abstract

The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (Calcineurin (Cn)) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium (K+)-stimulated expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomic analysis identified Nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4) as a target for Cn-mediated dephosphorylation. Deletion of NFATc4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATc4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATc4 directly regulates CYP11B2 expression. Thus, calcineurin controls aldosterone production via the Cn-NFATc4 pathway. Inhibition of Cn-NFATc4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus and the Cn-NFATc4 pathway may provide novel molecular targets to treat primary aldosteronism.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:24 July 2023
Deposited On:04 Jul 2023 13:12
Last Modified:26 Jun 2024 03:31
Publisher:American Society for Clinical Investigation
ISSN:2379-3708
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1172/jci.insight.157027
PubMed ID:37310791
Other Identification Number:PMCID: PMC10443813
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)