Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation

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 Clcn2 ^R180Q/+ mice, adrenal morphology is normal, but Cyp11b2 expression and plasma aldosterone levels are elevated. Male Clcn2 ^R180Q/+ 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 Clcn2 ^R180Q/+ 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.

Abstract

Mutations in the chloride channel ClC-2 have been associated with familial forms of hyperaldosteronism. Here, Schewe et al. generated a mouse model carrying the most common mutation found in patients and find it recapitulates key features of the disease, providing a unique tool for future studies on its pathogenesis.