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

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Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism.
Nature Communications ( IF 14.7 ) Pub Date : 2019-10-15 , DOI: 10.1038/s41467-019-12113-9
Corinna Göppner _{1,

2} , Ian J Orozco _{1,

2} , Maja B Hoegg-Beiler _{1,

2} , Audrey H Soria _{1,

2} , Christian A Hübner ₃ , Fabio L Fernandes-Rosa _{4,

5} , Sheerazed Boulkroun _{4,

5} , Maria-Christina Zennaro _{4,

5,

6} , Thomas J Jentsch _{1,

2,

7}

Affiliation

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.

中文翻译：

人CLCN2相关醛固酮增多症小鼠模型中高血压的发病机制。

人原发性醛固酮增多症（PA）可能是由几个离子通道基因的突变引起的，但缺乏复制这种情况的小鼠模型。我们现在显示，几乎所有已知的PA相关的CLCN2突变均显着增加ClC-2氯化物电流并产生敲入小鼠，其表达构成性开放的ClC-2 Cl-通道作为PA的小鼠模型。Clcn2op等位基因会强烈增加肾小球透明带细胞的氯化物传导，从而引起强烈的去极化作用并增加细胞质中Ca2 +的浓度。Clcn2op小鼠显示出人类PA的典型特征，包括在低肾素活性，明显的高血压和低血钾的情况下高血清醛固酮。这些症状在纯合子Clcn2op / op中比在杂合子Clcn2 + / op小鼠中更明显。这种差异归因于出乎意料的发现，即只有约50％的Clcn2 + / op透明带肾小球细胞被去极化。通过复制人类PA的基本特征，Clcn2op小鼠是研究该疾病潜在病理机制的有价值的模型。

更新日期：2019-10-16

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