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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. and Orozco, I.J. and Hoegg-Beiler, M.B. and Soria, A.H. and Hübner, C.A. and Fernandes-Rosa, F.L. and Boulkroun, S. and 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
Publisher:Nature Publishing Group
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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