Enhanced Ca signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model ( ).

Gain-of-function mutations in the gene (encoding the T-type calcium channel Ca3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice ( ). Adrenal morphology of both and mice was normal. mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal (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 mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. mice had elevated renal (renin-1) expression but normal adrenal levels, suggesting that in the absence of Ca3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, 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 Ca concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of Ca3.2 channel function can be compensated for in a chronic setting.