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


  • J. Schewe
  • E. Seidel
  • S. Forslund
  • L. Marko
  • J. Peters
  • D.N. Muller
  • C. Fahlke
  • G. Stölting
  • U. Scholl


  • Nature Communications


  • Nat Commun 10 (1): 5155


  • 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.