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

Julia Schewe, Eric Seidel, Sofia Forslund, Lajos Marko, Jörg Peters, Dominik N. Muller, Christoph Fahlke, Gabriel Stölting and Ute Scholl ()
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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
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
Sofia Forslund: Berlin Institute of Health (BIH)
Lajos Marko: Berlin Institute of Health (BIH)
Jörg Peters: Universitätsmedizin Greifswald
Dominik N. Muller: Berlin Institute of Health (BIH)
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13033-4

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