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

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Göppner, Corinna | Orozco, Ian, J | Hoegg-Beiler, Maja, B | Soria, Audrey, H | Hübner, Christian, A | Fernandes-Rosa, Fabio, L | Boulkroun, Sheerazed | Zennaro, Maria-Christina | Jentsch, Thomas, J

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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