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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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