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

• Published in: Nature communications Vol. 10; no. 1; pp. 5155 - 14
• Main Authors: Schewe, Julia, Seidel, Eric, Forslund, Sofia, Marko, Lajos, Peters, Jörg, Muller, Dominik N., Fahlke, Christoph, Stölting, Gabriel, Scholl, Ute
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.11.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/34; 38/71; 38/77; 64/60; 692/163/2743/1279; 692/308/1426; 82/1; Adrenal glands; Adrenal Glands - pathology; Aldosterone; Aldosterone - blood; Aldosterone synthase; Amino Acid Sequence; Animals; Base Sequence; Blood Pressure; Calcium; Chloride Channels - chemistry; Chloride Channels - genetics; Chloride ions; Chlorides; Chlorides - urine; CLC-2 Chloride Channels; Cytochrome P-450 CYP11B2 - metabolism; Depolarization; Disease Models, Animal; Efflux; Endocrine disorders; Female; Heterozygote; Homology; Humanities and Social Sciences; Hyperaldosteronism - blood; Hyperaldosteronism - physiopathology; Hyperaldosteronism - urine; Hypertension; Ion channels; Male; Mice, Inbred C57BL; Missense mutation; Morphology; multidisciplinary; Mutation; Mutation - genetics; Pathogenesis; Phenotype; Renin; Renin - blood; Science; Sodium; Sodium - urine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13033-4

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 Clcn2 R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2 R180Q/+ 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 Clcn2 R180Q/+ 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. Mutations in the chloride channel ClC-2 have been associated with familial forms of hyperaldosteronism. Here, Schewe et al. generated a mouse model carrying the most common mutation found in patients and find it recapitulates key features of the disease, providing a unique tool for future studies on its pathogenesis.