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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 17; pp. 1 - 11
• Main Authors: Seidel, Eric, Schewe, Julia, Zhang, Junhui, Dinh, Hoang An, Forslund, Sofia K., Markó, Lajos, Hellmig, Nicole, Peters, Jörg, Muller, Dominik N., Lifton, Richard P., Nottoli, Timothy, Stölting, Gabriel, Scholl, Ute I.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 27.04.2021
• Subjects: Age; Aldosterone; Aldosterone synthase; Angiotensin; Autonomy; Biological Sciences; Blood pressure; Calcium (intracellular); Calcium channels; Calcium channels (T-type); Calcium channels (voltage-gated); Calcium ions; Calcium signalling; Cellular manufacture; CRISPR; Diet; Endocrine disorders; Hypertension; Intracellular; Morphology; Mutation; Renin; Sodium
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2014876118

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.