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other·preclinical research, endocrinology, nephrology, biomedical research, cardiology·PMC10443813

Calcineurin regulates aldosterone production via dephosphorylation of NFATC4

JCI Insight · 9 authors, 8 centres

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TL;DR

Preclinical study showing that inhibition of calcineurin with tacrolimus abolishes potassium-stimulated CYP11B2 expression in NCI-H295R cells and mouse/human adrenal tissue, identifying NFATC4 as a key downstream effector.

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This preclinical study investigated calcineurin's role in aldosterone biosynthesis using NCI-H295R cells, ZG-specific CnB1 knockout mice, and ex vivo human adrenal tissue. Tacrolimus abolished potassium-stimulated CYP11B2 expression in NCI-H295R cells and ex vivo in mouse and human adrenal tissue. ZG-specific deletion of CnB1 diminished Cyp11b2 expression and disrupted K+-mediated aldosterone synthesis in mice. Phosphoproteomics identified NFATC4 as a Cn dephosphorylation target. NFATC4 deletion impaired K+-dependent CYP11B2 expression, while constitutively active NFATC4 increased it. Chromatin immunoprecipitation showed NFATC4 directly regulates CYP11B2. The findings may explain hyperkalemia in tacrolimus-treated patients and identify the Cn/NFATC4 axis as a potential therapeutic target for primary aldosteronism.

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other

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preclinical research

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ORIGINAL PAPER

PMC10443813

Calcineurin regulates aldosterone production via dephosphorylation of NFATC4

JCI Insight

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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-stimulated (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. Phosphoproteomics 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 regulated CYP11B2 expression. Thus, Cn 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.

CITATION EXPORT

Mesut Berber, Sining Leng, Agnieszka Wengi et al.. Calcineurin regulates aldosterone production via dephosphorylation of NFATC4. JCI Insight. (2023). https://doi.org/10.1172/jci.insight.157027

AUTHORS

9 · 8 CENTRES

Mesut Berber, Sining Leng, Agnieszka Wengi, Denise V. Winter, Alex Odermatt, Felix Beuschlein, Johannes Loffing, David T. Breault, David Penton

1Institute of Anatomy, University of Zurich, Switzerland.
2Swiss National Centre for Competence in Research “Kidney Control of Homeostasis” (NCCR Kidney.CH), Zurich, Switzerland.
3Department of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, USA.
4Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA.
5Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
6Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
7Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
8Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.