Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+ )
- PMID: 33879608
- PMCID: PMC8092574
- DOI: 10.1073/pnas.2014876118
Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+ )
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.
Copyright © 2021 the Author(s). Published by PNAS.
Conflict of interest statement
The authors declare no competing interest.
Figures
![Fig. 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig01.gif)
![Fig. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig02.gif)
![Fig. 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig03.gif)
![Fig. 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig04.gif)
![Fig. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig05.gif)
![Fig. 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig06.gif)
![Fig. 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8092574/bin/pnas.2014876118fig07.gif)
Similar articles
-
CaV3.2 (CACNA1H) in Primary Aldosteronism.Handb Exp Pharmacol. 2023;279:249-262. doi: 10.1007/164_2023_660. Handb Exp Pharmacol. 2023. PMID: 37311830 Review.
-
Cellular Pathophysiology of Mutant Voltage-Dependent Ca2+ Channel CACNA1H in Primary Aldosteronism.Endocrinology. 2020 Oct 1;161(10):bqaa135. doi: 10.1210/endocr/bqaa135. Endocrinology. 2020. PMID: 32785697
-
Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.Elife. 2015 Apr 24;4:e06315. doi: 10.7554/eLife.06315. Elife. 2015. PMID: 25907736 Free PMC article.
-
Somatic CACNA1H Mutation As a Cause of Aldosterone-Producing Adenoma.Hypertension. 2020 Mar;75(3):645-649. doi: 10.1161/HYPERTENSIONAHA.119.14349. Epub 2020 Jan 27. Hypertension. 2020. PMID: 31983310 Free PMC article.
-
SFE/SFHTA/AFCE consensus on primary aldosteronism, part 5: Genetic diagnosis of primary aldosteronism.Ann Endocrinol (Paris). 2016 Jul;77(3):214-9. doi: 10.1016/j.ando.2016.02.006. Epub 2016 Jun 15. Ann Endocrinol (Paris). 2016. PMID: 27315758
Cited by
-
Genetic variants and down-regulation of CACNA1H in pheochromocytoma.Endocr Relat Cancer. 2024 Jul 8;31(9):e230061. doi: 10.1530/ERC-23-0061. Print 2024 Sep 1. Endocr Relat Cancer. 2024. PMID: 38864697 Free PMC article.
-
T- and L-Type Calcium Channels Maintain Calcium Oscillations in the Murine Zona Glomerulosa.Hypertension. 2024 Apr;81(4):811-822. doi: 10.1161/HYPERTENSIONAHA.123.21798. Epub 2024 Feb 16. Hypertension. 2024. PMID: 38507511 Free PMC article.
-
Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities.JCI Insight. 2023 Oct 23;8(20):e162468. doi: 10.1172/jci.insight.162468. JCI Insight. 2023. PMID: 37698934 Free PMC article.
-
Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations Sufficient to Drive AngII (Angiotensin II)-Unresponsive Hyperaldosteronism.Hypertension. 2022 Nov;79(11):2552-2564. doi: 10.1161/HYPERTENSIONAHA.122.19557. Epub 2022 Sep 21. Hypertension. 2022. PMID: 36129175 Free PMC article.
-
Genetics of Primary Aldosteronism.Hypertension. 2022 May;79(5):887-897. doi: 10.1161/HYPERTENSIONAHA.121.16498. Epub 2022 Feb 10. Hypertension. 2022. PMID: 35139664 Free PMC article. Review.
References
-
- Spät A., Hunyady L., Control of aldosterone secretion: A model for convergence in cellular signaling pathways. Physiol. Rev. 84, 489–539 (2004). - PubMed
-
- Monticone S., et al. ., Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J. Am. Coll. Cardiol. 69, 1811–1820 (2017). - PubMed
-
- Funder J. W., et al. ., The management of primary aldosteronism: Case detection, diagnosis, and treatment: An endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 1889–1916 (2016). - PubMed
Publication types
MeSH terms
Substances
Supplementary concepts
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous