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Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation

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  • Julia Schewe

    (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin Berlin Institute of Health, Department of Nephrology and Medical Intensive Care
    Berlin Institute of Health (BIH)
    Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, BIH Center for Regenerative Therapies
    Heinrich-Heine-Universität Düsseldorf)

  • Eric Seidel

    (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin Berlin Institute of Health, Department of Nephrology and Medical Intensive Care
    Berlin Institute of Health (BIH)
    Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, BIH Center for Regenerative Therapies
    Heinrich-Heine-Universität Düsseldorf)

  • Sofia Forslund

    (Berlin Institute of Health (BIH)
    Max Delbruck Center for Molecular Medicine in the Helmholtz Association
    Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health)

  • Lajos Marko

    (Berlin Institute of Health (BIH)
    Max Delbruck Center for Molecular Medicine in the Helmholtz Association
    Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health)

  • Jörg Peters

    (Universitätsmedizin Greifswald)

  • Dominik N. Muller

    (Berlin Institute of Health (BIH)
    Max Delbruck Center for Molecular Medicine in the Helmholtz Association
    Experimental and Clinical Research Center, a cooperation of Charité-Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine
    Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health)

  • Christoph Fahlke

    (Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich)

  • Gabriel Stölting

    (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin Berlin Institute of Health, Department of Nephrology and Medical Intensive Care
    Berlin Institute of Health (BIH)
    Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, BIH Center for Regenerative Therapies
    Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich)

  • Ute Scholl

    (Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin Berlin Institute of Health, Department of Nephrology and Medical Intensive Care
    Berlin Institute of Health (BIH)
    Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, BIH Center for Regenerative Therapies
    Heinrich-Heine-Universität Düsseldorf)

Abstract

Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). Here, we report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation. In these Clcn2R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2R180Q/+ mice have increased aldosterone:renin ratios as well as elevated blood pressure levels. The counterpart knockout model (Clcn2−/−), in contrast, requires elevated renin levels to maintain normal aldosterone levels. Adrenal slices of Clcn2R180Q/+ mice show increased calcium oscillatory activity. Together, our work provides a knockin mouse model with a mild form of primary aldosteronism, likely due to increased chloride efflux and depolarization. We demonstrate a role of ClC-2 in normal aldosterone production beyond the observed pathophysiology.

Suggested Citation

  • Julia Schewe & Eric Seidel & Sofia Forslund & Lajos Marko & Jörg Peters & Dominik N. Muller & Christoph Fahlke & Gabriel Stölting & Ute Scholl, 2019. "Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13033-4
    DOI: 10.1038/s41467-019-13033-4
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    Cited by:

    1. Tao Ma & Lei Wang & Anping Chai & Chao Liu & Wenqiang Cui & Shuguang Yuan & Shannon Wing Ngor Au & Liang Sun & Xiaokang Zhang & Zhenzhen Zhang & Jianping Lu & Yuanzhu Gao & Peiyi Wang & Zhifang Li & Y, 2023. "Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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