CASZ1b is a novel transcriptional corepressor of mineralocorticoid receptor

Abstract

Aldosterone is a biological ligand for mineralocorticoid receptor (MR) that elevates blood pressure by promoting sodium reabsorption in the kidneys. However, the molecular mechanisms of aldosterone-MR-mediated transcription and the role of this transcription in hypertension remain largely unknown. In this study, we aimed to identify novel MR coregulators and elucidate one of the molecular mechanisms of hypertension. We purified MR-interacting factors from HEK293F cells stably expressing FLAG-MR through a biochemical approach and identified the zinc finger protein castor homolog 1 isoform b (CASZ1b) as a candidate novel MR coregulator via liquid chromatography—tandem mass spectrometry analysis. The CASZ1 gene has been implicated in hypertension in genome-wide single-nucleotide polymorphism studies, but its role in the development of hypertension remains unclear. We found that CASZ1b colocalized with MR in the kidneys and interacted with MR in an aldosterone-dependent manner. In luciferase assays using HEK293F cells, overexpression of CASZ1b reduced aldosterone-dependent MR transcriptional activity by ~50%. In contrast, knockdown of CASZ1b via RNA interference increased the expression levels of the aldosterone-induced MR target genes epithelial Na+ channel-α (ENaCα) and serum/glucocorticoid regulated kinase 1 (SGK1) by approximately twofold and 2.3-fold, respectively. Upon aldosterone-MR binding, CASZ1b interacted with MR and formed a protein complex with nucleosome remodeling deacetylase (Mi-2/NuRD), a corepressor complex with chromatin remodeling and histone deacetylation activity, which suppressed ENaCα and SGK1. These findings reveal a critical role of CASZ1b in regulating MR-mediated transcriptional activity and provide new insights into the pathophysiology of hypertension.

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Acknowledgements

We express our deep appreciation for all the help provided by Dr S Kato. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by JSPS KAKENHI grant number 17K09734 (to KY), the Keio Gijuku Academic Development Funds (to KY and IK), the Japan Foundation for Applied Enzymology (to KY), the Smoking Research Foundation (to KY and IK), Eli Lilly (to KY), the Takeda Science Foundation (to IK), and the Yamaguchi Endocrine Research Foundation (to IK).

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Correspondence to Kenichi Yokota.

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All animal procedures were approved by the institutional review board of the Animal Care and Use Committee and were conducted in compliance with the animal experimentation guidelines of Keio University School of Medicine.

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Yokota, K., Shibata, H., Kurihara, I. et al. CASZ1b is a novel transcriptional corepressor of mineralocorticoid receptor. Hypertens Res (2020). https://doi.org/10.1038/s41440-020-00562-5

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Keywords

  • Aldosterone
  • CASZ1b
  • Hypertension
  • Mineralocorticoid receptor

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