Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

Göppner, C.; Orozco, I.J.; Hoegg-Beiler, M.B.; Soria, A.H.; Hübner, C.A.; Fernandes-Rosa, F.L.; Boulkroun, S.; Zennaro, M.C.; Jentsch, T.J.

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

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Item Type:	Article
Title:	Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism
Creators Name:	Göppner, C., Orozco, I.J., Hoegg-Beiler, M.B., Soria, A.H., Hübner, C.A., Fernandes-Rosa, F.L., Boulkroun, S., Zennaro, M.C. and Jentsch, T.J.
Abstract:	Human primary aldosteronism (PA) can be caused by mutations in several ion channel genes but mouse models replicating this condition are lacking. We now show that almost all known PA-associated CLCN2 mutations markedly increase ClC-2 chloride currents and generate knock-in mice expressing a constitutively open ClC-2 Cl(−) channel as mouse model for PA. The Clcn2(op) allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca(2+) concentration. Clcn2(op) mice display typical features of human PA, including high serum aldosterone in the presence of low renin activity, marked hypertension and hypokalemia. These symptoms are more pronounced in homozygous Clcn2(op/op) than in heterozygous Clcn2+/op mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2(+/op) zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2(op) mice are a valuable model to study the pathological mechanisms underlying this disease.
Keywords:	Animal Disease Models, Chloride Channels, Gene Knock-In Techniques, Heterozygote, Homozygote, Hyperaldosteronism, Hypertension, Hypokalemia, Mutation, Zona Glomerulosa, Animals, Mice
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	10
Number:	1
Page Range:	4678
Date:	15 October 2019
Official Publication:	https://doi.org/10.1038/s41467-019-12113-9
PubMed:	View item in PubMed

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