Helmholtz Gemeinschaft


Enhanced Ca(2+) signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h(M1560V/+))

PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supplementary Material)

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. and Schewe, J. and Zhang, J. and Dinh, H.A. and Forslund, S.K. and Markó, L. and Hellmig, N. and Peters, J. and Muller, D.N. and Lifton, R.P. and Nottoli, T. and 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
Publisher:National Academy of Sciences
Page Range:e2014876118
Date:27 April 2021
Official Publication:https://doi.org/10.1073/pnas.2014876118
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library