Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+ )

Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2014876118. doi: 10.1073/pnas.2014876118.

Abstract

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel CaV3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1hM1560V/+ knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h-/- ). Adrenal morphology of both Cacna1hM1560V/+ and Cacna1h-/- mice was normal. Cacna1hM1560V/+ mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1hM1560V/+ mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h-/- mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of CaV3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1hM1560V/+ adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca2+ concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of CaV3.2 channel function can be compensated for in a chronic setting.

Keywords: CaV3.2; adrenal gland; calcium imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / biosynthesis
  • Animals
  • Blood Pressure
  • Calcium Channels / genetics
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism
  • Calcium Signaling / physiology*
  • Cytochrome P-450 CYP11B2 / metabolism
  • Disease Models, Animal
  • Gain of Function Mutation
  • Hyperaldosteronism / metabolism
  • Hyperaldosteronism / physiopathology*
  • Hypertension / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation

Substances

  • Cacna1h protein, mouse
  • Calcium Channels
  • Calcium Channels, T-Type
  • Aldosterone
  • Cytochrome P-450 CYP11B2

Supplementary concepts

  • Familial Hyperaldosteronism