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

Nat Commun. 2019 Nov 14;10(1):5155. doi: 10.1038/s41467-019-13033-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / pathology
  • Aldosterone / blood*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blood Pressure*
  • CLC-2 Chloride Channels
  • Chloride Channels / chemistry
  • Chloride Channels / genetics*
  • Chlorides / urine
  • Cytochrome P-450 CYP11B2 / metabolism
  • Disease Models, Animal
  • Female
  • Heterozygote
  • Hyperaldosteronism / blood*
  • Hyperaldosteronism / physiopathology*
  • Hyperaldosteronism / urine
  • Male
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Phenotype
  • Renin / blood
  • Sodium / urine

Substances

  • CLC-2 Chloride Channels
  • Chloride Channels
  • Chlorides
  • Clcn2 protein, mouse
  • Aldosterone
  • Sodium
  • Cytochrome P-450 CYP11B2
  • Renin

Supplementary concepts

  • Familial Hyperaldosteronism