Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation
Authors
- J. Schewe
- E. Seidel
- S. Forslund
- L. Marko
- J. Peters
- D.N. Muller
- C. Fahlke
- G. Stölting
- U. Scholl
Journal
- Nature Communications
Citation
- Nat Commun 10 (1): 5155
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.