气候变化领域集成服务门户(CCPortal): Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)

CCPortal

DOI	10.1073/pnas.2014876118
	Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)
	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.; Scholl U.I.
发表日期	2021
ISSN	00278424
卷号	118 期号:17
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Adrenal gland; CaV3.2; Calcium imaging
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179742
作者单位	Department of Nephrology, Charité–Universitätsmedizin Berlin, Berlin, 10115, Germany; Berlin Institute of Health, Charité–Universitätsmedizin Berlin, Berlin, 10117, Germany; Center for Regenerative Therapies, Berlin Institute of Health, Charité–Universitätsmedizin Berlin, Berlin, 13353, Germany; Department of Nephrology, School of Medicine, Heinrich-Heine Universität Düsseldorf, Düsseldorf, 40225, Germany; Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, United States; Max Delbruck Center for Molecular Medicine, Helmholtz Association of German Research Centers, Berlin, 13125, Germany; Experimental and Clinical Research Center, Max Delbruck Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, Berlin, 13125, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, 13019, Germany; Department of Physiology, Universitätsmedizin Greifswald, Greifswald, 17475, Germany; Laboratory of Human Genetics and Genomics, The Rockefeller Universi...
推荐引用方式 GB/T 7714	Seidel E.,Schewe J.,Zhang J.,et al. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)[J],2021,118(17).
APA	Seidel E..,Schewe J..,Zhang J..,Dinh H.A..,Forslund S.K..,...&Scholl U.I..(2021).Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+).Proceedings of the National Academy of Sciences of the United States of America,118(17).
MLA	Seidel E.,et al."Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)".Proceedings of the National Academy of Sciences of the United States of America 118.17(2021).