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

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 Clchannel as mouse model for PA. The Clcn2allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Caconcentration. Clcn2mice 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 Clcn2than in heterozygous Clcn2mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2mice are a valuable model to study the pathological mechanisms underlying this disease.