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Salt-sensitive hypertension in circadian clock–deficient Cry-null mice involves dysregulated adrenal Hsd3b6

Nature Medicine volume 16, pages 6774 (2010) | Download Citation

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Abstract

Malfunction of the circadian clock has been linked to the pathogenesis of a variety of diseases. We show that mice lacking the core clock components Cryptochrome-1 (Cry1) and Cryptochrome-2 (Cry2) (Cry-null mice) show salt-sensitive hypertension due to abnormally high synthesis of the mineralocorticoid aldosterone by the adrenal gland. An extensive search for the underlying cause led us to identify type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6) as a new hypertension risk factor in mice. Hsd3b6 is expressed exclusively in aldosterone-producing cells and is under transcriptional control of the circadian clock. In Cry-null mice, Hsd3b6 messenger RNA and protein levels are constitutively high, leading to a marked increase in 3β-hydroxysteroid dehydrogenase-isomerase (3β-HSD) enzymatic activity and, as a consequence, enhanced aldosterone production. These data place Hsd3b6 in a pivotal position through which circadian clock malfunction is coupled to the development of hypertension. Translation of these findings to humans will require clinical examination of human HSD3B1 gene, which we found to be functionally similar to mouse Hsd3b6.

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Acknowledgements

We thank T. Ono, A. Hirasawa, T. Koshimizu, K. Terasawa, H. Nishinaga, M. Sato, Y. Yamaguchi, M. Matsuo, J.M. Fustin, K. Toida, H. Sei and K. Ishimura for technical support and valuable discussion. We also thank T. Michel for critical reading of the manuscript. This work was supported in part by the Specially Promoted Research (to H.O.) and Grant-in-Aid for Young Scientists (to M.D.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and grants from Nakatomi Foundation, SRF (to H.O.), Senri Life Science Foundation, Takeda Science Foundation (to M.D.) and the Netherlands Organization of Scientific research, ZonMW Vici 918.36.619 (to G.T.J.v.d.H.). Trilostane was a generous gift from Mochida Pharmaceutical. Eplerenone was a generous gift from Pfizer.

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Affiliations

  1. Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.

    • Masao Doi
    • , Yukari Takahashi
    • , Rie Komatsu
    • , Fumiyoshi Yamazaki
    • , Hiroyuki Yamada
    •  & Hitoshi Okamura
  2. Laboratory of Integrative Brain Sciences, Department of Biology, Faculty of Education and Integrated Arts and Sciences, Waseda University, Shinjuku-ku, Tokyo, Japan.

    • Shogo Haraguchi
    •  & Kazuyoshi Tsutsui
  3. Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.

    • Noriaki Emoto
  4. Department of Systems Bioscience for Drug Discovery, Kyoto University, Sakyo-ku, Kyoto, Japan.

    • Yasushi Okuno
  5. Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.

    • Gozoh Tsujimoto
  6. Department of Urology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.

    • Akihiro Kanematsu
    •  & Osamu Ogawa
  7. Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan.

    • Takeshi Todo
  8. Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Gijsbertus T J van der Horst

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Contributions

M.D. and H.O. designed the research; A.K., O.O., T.T. and G.T.J.v.d.H. supplied the experimental materials; M.D., Y.T., R.K., F.Y., H.Y., S.H., K.T. and H.O. acquired the data; M.D., N.E., Y.O., G.T., K.T. and H.O. analyzed the data; and M.D., G.T.J.v.d.H. and H.O. drafted the manuscript.

Corresponding author

Correspondence to Hitoshi Okamura.

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DOI

https://doi.org/10.1038/nm.2061