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Lysine-specific demethylase 1 as a corepressor of mineralocorticoid receptor

Hypertension Research volume 45, pages 641–649 (2022)Cite this article

Abstract

Mineralocorticoid receptor (MR) and its ligand aldosterone play a central role in controlling blood pressure by promoting sodium reabsorption in the kidney. Coregulators are recruited to regulate the activation of steroid hormone receptors. In our previous study, we identified several new candidates for MR coregulators through liquid chromatography-tandem mass spectrometry analysis using a biochemical approach. Lysine-specific demethylase 1 (LSD1) was identified as a candidate. The relationship between LSD1 and salt-sensitive hypertension has been reported; however, the role of MR in this condition is largely unknown. Here, we investigated the functions of LSD1 as a coregulator of MR. First, a coimmunoprecipitation assay using HEK293F cells showed specific interactions between MR and LSD1. A chromatin immunoprecipitation study demonstrated LSD1 recruitment to the gene promoter of epithelial Na+ channel (ENaC), a target gene of MR. Reduced LSD1 expression by treatment with shRNA potentiated the hormonal activation of ENaC and serum/glucocorticoid-regulated kinase 1, another target gene of MR, indicating that LSD1 is a corepressor of MR. In an animal study, mice with kidney-specific LSD1 knockout (LSD1flox/floxKSP-Cre mice) developed hypertension after a high-salt diet without elevation of aldosterone levels, which was counteracted by cotreatment with spironolactone, an MR antagonist. In conclusion, our in vitro and in vivo studies demonstrated that LSD1 is a newly identified corepressor of MR.

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Funding

This research was supported by JSPS KAKENHI (grant number: 18K08250) (to S.K.) and the Smoking Research Foundation (to H.I.) and partly supported by JSPS KAKENHI (Grant number: 19K08713) (to I.K.), JSPS KAKENHI (Grant number: 18K16007) (to A.M.), JSPS KAKENHI (Grant number: 19K17992) (to Y.M.), JSPS KAKENHI (Grant number: 21K08236) (to K.Y.), JSPS KAKENHI (Grant number: 20K17256) (to M.K.), and the Research Committee on Disorders of Adrenal Hormones, a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan (Nanjiseisikkanseisakukenkyujigyo [20FC1020]) (to I.K.)

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Authors and Affiliations

  1. Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

    Nao Kohata, Isao Kurihara, Kenichi Yokota, Sakiko Kobayashi, Ayano Murai-Takeda, Yuko Mitsuishi, Toshifumi Nakamura, Mitsuha Morisaki, Takahide Kozuma, Takuto Torimitsu, Miki Kawai & Hiroshi Itoh

  2. Department of Medical Education, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Isao Kurihara

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Kohata, N., Kurihara, I., Yokota, K. et al. Lysine-specific demethylase 1 as a corepressor of mineralocorticoid receptor. Hypertens Res 45, 641–649 (2022). https://doi.org/10.1038/s41440-022-00859-7

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