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| Item Type: | Article |
|---|---|
| Title: | Enhanced Ca(2+) signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h(M1560V/+)) |
| Creators Name: | Seidel, E., Schewe, J., Zhang, J., Dinh, H.A., Forslund, S.K., Markó, L., Hellmig, N., Peters, J., Muller, D.N., Lifton, R.P., Nottoli, T., Stölting, G. and Scholl, U.I. |
| Abstract: | Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel Ca(V)3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1h(M1560V/+) knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h(-/-)). Adrenal morphology of both Cacna1h(M1560V/+) and Cacna1h(-/-) mice was normal. Cacna1h(M1560V/+) 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 Cacna1h(M1560V/+) 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 Ca(V)3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1h(M1560V/+) 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(2+) 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 Ca(V)3.2 channel function can be compensated for in a chronic setting. |
| Keywords: | Ca(V)3.2, Calcium Imaging, Adrenal Gland, Animals, Mice |
| Source: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Volume: | 118 |
| Number: | 17 |
| Page Range: | e2014876118 |
| Date: | 27 April 2021 |
| Official Publication: | https://doi.org/10.1073/pnas.2014876118 |
| PubMed: | View item in PubMed |
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