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Nat Commun. 2019 Oct 15;10(1):4678. doi: 10.1038/s41467-019-12113-9.

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

Author information

1
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
2
Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
3
Institut für Humangenetik, Universitätsklinikum Jena, Jena, Germany.
4
INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France.
5
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
6
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
7
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. Jentsch@fmp-berlin.de.
8
Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany. Jentsch@fmp-berlin.de.
9
NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany. Jentsch@fmp-berlin.de.

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 Clcn2op allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca2+ concentration. Clcn2op 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 Clcn2op/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, Clcn2op mice are a valuable model to study the pathological mechanisms underlying this disease.

PMID:
31615979
PMCID:
PMC6794291
DOI:
10.1038/s41467-019-12113-9
[Indexed for MEDLINE]
Free PMC Article

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