Abstract
Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). Here, we report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation. In these Clcn2R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2R180Q/+ mice have increased aldosterone:renin ratios as well as elevated blood pressure levels. The counterpart knockout model (Clcn2−/−), in contrast, requires elevated renin levels to maintain normal aldosterone levels. Adrenal slices of Clcn2R180Q/+ mice show increased calcium oscillatory activity. Together, our work provides a knockin mouse model with a mild form of primary aldosteronism, likely due to increased chloride efflux and depolarization. We demonstrate a role of ClC-2 in normal aldosterone production beyond the observed pathophysiology.
Highlights
Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II)
Known forms are inherited in an autosomal−dominant fashion and include familial hyperaldosteronism type I (FH-I) with mutations in CYP11B217,18, FH-III due to mutations in the potassium channel KCNJ59,19 and FH-IV
Burst duration was not significantly altered (Supplementary Fig. 8b), and within bursts, the spiking frequency did not significantly differ between Clcn2R180Q/+ mice and controls (Supplementary Fig. 8c). These results suggest that the augmented ClC-2 activity in Clcn2R180Q/+ mice mainly increases the likelihood of initiating bursting activity in the presence of angiotensin II (AT-II), likely through depolarization compared to wildtype controls
Summary
Gain-of-function mutations in the chloride channel ClC-2 were recently described as a cause of familial hyperaldosteronism type II (FH-II). We report the generation of a mouse model carrying a missense mutation homologous to the most common FH-II-associated CLCN2 mutation In these Clcn2R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Excessive aldosterone production despite suppressed plasma renin activity and normal or low extracellular potassium levels (relative autonomy) is characteristic of primary aldosteronism (PA), the most common cause of secondary hypertension[3,4]. It accounts for about 6% of hypertensive patients in primary care and about 10% in specialized hypertension centers[5,6]. NA1D) that is expressed in the central nervous system are found in a syndrome of PA, seizures, and neurologic abnormalities[10]
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