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

doi:10.1073/pnas.2014876118

. 2021 Apr 27;118(17):e2014876118.

doi: 10.1073/pnas.2014876118.

Enhanced Ca²⁺ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h^M1560V/+ )

Eric Seidel^{1

2

3

4}, Julia Schewe^{1

2

3

4}, Junhui Zhang⁵, Hoang An Dinh^{1

2

3}, Sofia K Forslund^{2

6

7

8}, Lajos Markó^{2

6

7}, Nicole Hellmig^{1

2

3}, Jörg Peters⁹, Dominik N Muller^{2

6

7}, Richard P Lifton^{10

11}, Timothy Nottoli¹², Gabriel Stölting^{1

2

3}, Ute I Scholl^{13

2

3

4}

Affiliations

¹ Department of Nephrology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany.
² Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
³ Center for Regenerative Therapies, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
⁴ Department of Nephrology, School of Medicine, Heinrich-Heine Universität Düsseldorf, 40225 Düsseldorf, Germany.
⁵ Department of Genetics, Yale University School of Medicine, New Haven, CT 06519.
⁶ Max Delbruck Center for Molecular Medicine, Helmholtz Association of German Research Centers, 13125 Berlin, Germany.
⁷ Experimental and Clinical Research Center, Max Delbruck Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany.
⁸ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13019 Berlin, Germany.
⁹ Department of Physiology, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
¹⁰ Department of Genetics, Yale University School of Medicine, New Haven, CT 06519; rickl@rockefeller.edu ute.scholl@charite.de.
¹¹ Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.
¹² Section of Comparative Medicine, Yale Genome Editing Center, Yale University School of Medicine, New Haven, CT 06519.
¹³ Department of Nephrology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany; rickl@rockefeller.edu ute.scholl@charite.de.

PMID: 33879608
PMCID: PMC8092574
DOI: 10.1073/pnas.2014876118

Enhanced Ca²⁺ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h^M1560V/+ )

Eric Seidel et al. Proc Natl Acad Sci U S A. 2021.

. 2021 Apr 27;118(17):e2014876118.

doi: 10.1073/pnas.2014876118.

Authors

Affiliations

¹ Department of Nephrology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany.
² Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
³ Center for Regenerative Therapies, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
⁴ Department of Nephrology, School of Medicine, Heinrich-Heine Universität Düsseldorf, 40225 Düsseldorf, Germany.
⁵ Department of Genetics, Yale University School of Medicine, New Haven, CT 06519.
⁶ Max Delbruck Center for Molecular Medicine, Helmholtz Association of German Research Centers, 13125 Berlin, Germany.
⁷ Experimental and Clinical Research Center, Max Delbruck Center for Molecular Medicine, Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany.
⁸ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13019 Berlin, Germany.
⁹ Department of Physiology, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
¹⁰ Department of Genetics, Yale University School of Medicine, New Haven, CT 06519; rickl@rockefeller.edu ute.scholl@charite.de.
¹¹ Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.
¹² Section of Comparative Medicine, Yale Genome Editing Center, Yale University School of Medicine, New Haven, CT 06519.
¹³ Department of Nephrology, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany; rickl@rockefeller.edu ute.scholl@charite.de.

PMID: 33879608
PMCID: PMC8092574
DOI: 10.1073/pnas.2014876118

Abstract

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel Ca_V3.2) 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_V3.2, 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 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 Ca_V3.2 channel function can be compensated for in a chronic setting.

Keywords: CaV3.2; adrenal gland; calcium imaging.

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Conflict of interest statement

The authors declare no competing interest.

Figures

**Fig. 1.**
Generation of *Cacna1h*^M1560V/+ and *Cacna1h*^−/− mouse models. (A) Alignment of *Mus musculus* and *Homo sapiens* genomic and amino acid sequences surrounding human Met1549 (box) mutated in FH-IV. Identical nucleotides are shown in yellow. The protein sequence is completely conserved. (B) Representation of the mouse *Cacna1h* locus targeted on exon 25. Sequences of protospacer used to target Cas9 nuclease to exon 25 and repair template used to introduce *Cacna1h*^M1560V/+ via homology-directed repair are listed below target sequence. The guide binding site is underlined, and intended mutations (including three silent mutations) are shown in red letters. (C, *Upper*) Sanger sequences of genomic DNA (gDNA, from ear biopsies) from a WT control, a *Cacna1h*^M1560V/+ mouse, and a *Cacna1h*^−/− mouse (knockout). (*Lower*) Sanger sequences of adrenal complementary DNA (cDNA) from the identical animals shown above, demonstrating adrenal expression of the mutant alleles. Bases adjacent to the 8-bp deletion in *Cacna1h*^−/− are underlined.

**Fig. 2.**
Adrenal glands of *Cacna1h*^M1560V/+ and *Cacna1h*^−/− mice show unchanged morphology. (A) Adrenal weight (normalized to body weight) is unchanged between WT, *Cacna1h*^M1560V/+, and *Cacna1h*^−/− mice (WT: n = 21; M1560V: n = 29; P = 0.69; knockout [KO]: n = 17; P = 0.17; Kruskal–Wallis test with Dunn’s multiple comparisons test [MCP]). (B) Adrenal expression of *Cacna1h* is not changed in *Cacna1h*^M1560V/+ compared to WT (M1560V: n = 41; WT: n = 40; P = 0.95; unpaired two-tailed t test of log-transformed fold-change). (C) *Cacna1h* expression is unchanged between WT and *Cacna1h*^M1560V/+ in both sexes (male WT: n = 24; male M1560V: n = 17; P > 0.99; female WT: n = 16; female M1560V: n = 24; P > 0.99; Kruskal–Wallis test with Dunn’s MCP of log-transformed fold-change). All data are shown as box plots (box, interquartile range; whiskers, 1.5 times the interquartile range; line, median; dots, outliers); n values represent animals. ns, P > 0.05. (D and E) H&E staining of adrenal sections show unaltered morphology of *Cacna1h*^M1560V/+ and *Cacna1h*^−/− mice compared to WT (three mice each, representative images, pictures of male mice at 15 to 16 wk of age are shown). C, capsule; F, fasciculata; G, glomerulosa; M, medulla. (Scale bars, 500 μm in D and 100 μm in E.).

**Fig. 3.**
Adrenal sections of *Cacna1h*^M1560V/+ and *Cacna1h*^−/− mice show normal *Cyp11b2* staining. (A and B) In situ hybridization with corresponding negative controls (see *Materials and Methods*). One of four to five animals of each genotype is shown. C: capsule; F: fasciculata; G, glomerulosa; M: medulla. (Scale bars, 500 μm in A and 100 μm in B.)

**Fig. 4.**
*Cacna1h*^M1560V/+ mice have elevated adrenal *Cyp11b2* expression. (A) Adrenal *Cyp11b2* expression is increased in *Cacna1h*^M1560V/+ mice during NSD (WT: n = 43; *Cacna1h*^M1560V/+: n = 43; P = 0.004 vs. WT; KO: n = 11; P = 0.996 vs. WT; one-way ANOVA with Dunnett’s MCP). (B) *Cyp11b2* expression is only increased in male *Cacna1h*^M1560V/+ mice (male WT: n = 24; male *Cacna1h*^M1560V/+: n = 18; P = 0.004; female WT: n = 19; female *Cacna1h*^M1560V/+: n = 25; P = 0.294; one-way ANOVA and Sidak’s MCP). (C) Adrenal *Cyp11b2* expression remains elevated in *Cacna1h*^M1560V/+ mice during HSD (WT: n = 12; *Cacna1h*^M1560V/+: n = 9; P = 0.008; unpaired two-tailed t test). (D) Plasma aldosterone is not significantly changed in *Cacna1h*^M1560V/+ mice or *Cacna1h*^−/− mice during NSD (WT: n = 42; *Cacna1h*^M1560V/+: n = 41; P = 0.090; KO: n = 13; P = 0.895; Kruskal–Wallis test and Dunn’s MCP). (E) Plasma aldosterone is significantly increased in male, but not in female *Cacna1h*^M1560V/+ mice (male WT: n = 23; male *Cacna1h*^M1560V/+: n = 17; P = 0.016; female WT: n = 19; female *Cacna1h*^M1560V/+: n = 24; P > 0.999; Kruskal–Wallis test and Dunn’s MCP). (F) There is no significant difference in aldosterone between *Cacna1h*^M1560V/+ and WT during HSD (WT: n = 8; *Cacna1h*^M1560V/+: n = 9; P = 0.393; unpaired two-tailed t test). Box plots (box, interquartile range; whiskers, 1.5 times the interquartile range; line, median; dots, outliers) are shown in the figure; n values are animals. ns, P > 0.05; *P < 0.05; **P < 0.01.

**Fig. 5.**
*Cacna1h*^−/− mice show elevated *Ren1* expression; *Cacna1h*^M1560V/+ mice have elevated ARRs. (*A–C*) Kidney expression of *Ren1* is increased in KO mice but not significantly changed in *Cacna1h*^M1560V/+ mice during NSD (WT: n = 43; *Cacna1h*^M1560V/+: n = 43; P = 0.095 vs. WT; KO: n = 11; P = 0.026 vs. WT; one-way ANOVA and Dunnett’s MCP; male WT: n = 24; male *Cacna1h*^M1560V/+: n = 18; P = 0.688; female WT: n = 19; female *Cacna1h*^M1560V/+: n = 25; P = 0.078; one-way ANOVA and Sidak’s MCP) or HSD (WT: n = 12; *Cacna1h*^M1560V/+: n = 9; P = 0.425; Mann–Whitney test). (*D–F*) PRC is not significantly changed in *Cacna1h*^M1560V/+ and *Cacna1h*^−/− mice during NSD (WT: n = 39; *Cacna1h*^M1560V/+: n = 40; P = 0.115; KO: n = 13; P > 0.999; Kruskal–Wallis test and Dunn’s MCP). In subgroup analysis, PRC is decreased in female *Cacna1h*^M1560V/+ mice only (male WT: n = 22; male *Cacna1h*^M1560V/+: n = 17; P = 0.821; female WT: n = 17; female *Cacna1h*^M1560V/+: n = 23; P = 0.046; Kruskal–Wallis test and Dunn’s MCP). PRC is reduced in *Cacna1h*^M1560V/+ mice during HSD (WT: n = 10; *Cacna1h*^M1560V/+: n = 8; P = 0.008; unpaired two-tailed t test). (G–I) The ratio of *Cyp11b2* and *Ren1* expression was calculated using fold-change. (G) Expression ratio is significantly increased in *Cacna1h*^M1560V/+ compared to WT mice and not significantly changed in *Cacna1h*^−/− compared to WT (WT: n = 43; M1560V: n = 43; P = 0.005; *Cacna1h*^−/−: n = 11, P = 0.176; Kruskal–Wallis test, Dunn’s MCP). (H) The ratio is significantly increased in male *Cacna1h*^M1560V/+ mice compared to WT (WT: n = 24; *Cacna1h*^M1560V/+: n = 18; P = 0.010; Kruskal–Wallis test and Dunn’s MCP), but not in female mice (WT: n = 19; *Cacna1h*^M1560V/+: n = 25; P = 0.074; Kruskal–Wallis test and Dunn’s MCP). (I) After HSD, the ratio is significantly increased in *Cacna1h*^M1560V/+ mice compared to WT (WT: n = 12; *Cacna1h*^M1560V/+: n = 9; P = 0.009; Mann–Whitney test). (J) ARRs (calculated using plasma aldosterone levels and PRC) are increased in *Cacna1h*^M1560V/+ mice compared to WT under NSD (WT: n = 39; M1560V: n = 39; P = 0.033; Kruskal–Wallis test with Dunn’s MCP). In *Cacna1h*^−/− mice, ARR is not significantly changed compared to WT (WT: n = 39; KO: n = 13; P = 0.540; Kruskal–Wallis test, Dunn’s MCP). (K) ARR levels are not significantly changed in subgroup analyses (male WT: n = 22; M1560V: n = 17; P = 0.070; female mice WT: n = 17; M1560V: n = 22; P = 0.353; Kruskal–Wallis test, Dunn’s MCP). (L) After HSD, ARR remains elevated in *Cacna1h*^M1560V/+ mice (WT: n = 8; *Cacna1h*^M1560V/+: n = 8; P = 0.015; unpaired two-tailed t test). All data are shown in box plots (box, interquartile range; whiskers, 1.5 times the interquartile range; line, median; dots, outliers); n values are animals. ns, P > 0.05; *P < 0.05; **P < 0.01.

**Fig. 6.**
Blood pressure is higher in *Cacna1h*^M1560V/+ mice. Blood pressure (BP) and heart rate (HR) of animals were assessed during NSD and HSD through common carotid artery telemetry. Graphs show loess regressions of BP or HR of WT (black, n = 8 animals on NSD and n = 7 on HSD) and *Cacna1h*^M1560V/+ (red, n = 7 animals for both conditions) mice. Gray intervals denote 95% confidence intervals for loess regressions. Horizontal axis shows time, with black lines noting nights (6:00 PM to 6:00 AM). Horizontal lines show means for the entire NSD and HSD period, respectively, for WT (black) and *Cacna1h*^M1560V/+ (red dashed) animals. Nested-model likelihood ratio comparisons revealed significantly higher SBP (P = 0.001) and MAP (P = 0.002) during NSD; DBP (P = 0.139) and HR (P = 0.135) were not significantly changed. n = 9 WT, n = 8 *Cacna1h*^M1560V/+ animals. Mean ± SD values: NSD-SBP, 115.9 ± 13.7 mmHg (WT), 124.2 ± 14.7 mmHg (*Cacna1h*^M1560V/+); NSD-DBP, 85.0 ± 12.1 mmHg (WT) and 87.7 ± 11.9 mmHg (*Cacna1hM*^1560V/+); NSD-MAP, 99.9 ± 12.5 mmHg (WT) and 105.2 ± 13.1 mmHg (*Cacna1h*^M1560V/+); NSD-HR, 462.2 ± 100.4 beats per minute (BPM, WT) and 482.1 ± 111.1 BPM (*Cacna1h*^M1560V/+). Similarly, during HSD, SBP (P = 0.0008) and MAP (P = 0.021) were increased in *Cacna1h*^M1560V/+ mice, while DBP (P = 0.65) and HR (P = 0.92) were unchanged. One WT mouse failed HSD recording. Mean ± SD: HSD-SBP, 122.2 ± 15.7 mmHg (WT) and 128.8 ± 18.1 mmHg (*Cacna1h*^M1560V/+); HSD-DBP, 88.2 ± 13.4 mmHg (WT) and 89.2 ± 13.7 mmHg (*Cacna1hM*^1560V/+); HSD-MAP, 104.5 ± 14.2 mmHg (WT) and 108.0 ± 15.4 mmHg (*Cacna1h*^M1560V/+); HSD-HR, 450.9 ± 92.3 BPM (WT) and 451.8 ± 100.9 BPM (*Cacna1h*^M1560V/+).

**Fig. 7.**
*Cacna1h*^M1560V/+ mice have higher intracellular calcium concentrations than controls. (A and B) Representative average projections over 20 s from a WT or M1560V adrenal slice stained with Fura-2 AM (*Upper*). Intensity corresponds to the intracellular calcium concentration. (Scale bars, 10 µm.) The concentration changes of one representative cell each (both at 5 mM K⁺ and 1 nM Ang II) are shown below. The trace is color-coded to represent baseline concentrations (purple), spiking activity (black) and peak concentrations (center of red circles). (C) Baseline as well as peak intracellular calcium concentrations are higher in *Cacna1h*^M1560V/+ compared to WT mice under all tested conditions. (D) The mean overall intracellular calcium concentrations (including baseline, spiking and peak segments) are also elevated in *Cacna1h*^M1560V/+ mice. (E) Mean frequencies of calcium spikes during the corresponding perfusions are lower in *Cacna1h*^M1560V/+ than in WT mice at supraphysiological concentrations of Ang II only. P values (likelihood ratio test of linear mixed models) are indicated as follows: ns, P ≥ 0.05; *P < 0.05; **P < 0.01; ***P < 0.001. See *SI Appendix*, Table S1 for statistical information. Data in C and D are shown as bars (mean) ± SD. Data in E are shown in box plots (box, interquartile range; whiskers, 1.5 times the interquartile range; line, median; dots, outliers).

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References

1. Hattangady N. G., Olala L. O., Bollag W. B., Rainey W. E., Acute and chronic regulation of aldosterone production. Mol. Cell. Endocrinol. 350, 151–162 (2012). - PMC - PubMed
1. Spät A., Hunyady L., Control of aldosterone secretion: A model for convergence in cellular signaling pathways. Physiol. Rev. 84, 489–539 (2004). - PubMed
1. 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
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1. Nanba K., et al. ., Targeted molecular characterization of aldosterone-producing adenomas in White Americans. J. Clin. Endocrinol. Metab. 103, 3869–3876 (2018). - PMC - PubMed

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[1] Hattangady N. G., Olala L. O., Bollag W. B., Rainey W. E., Acute and chronic regulation of aldosterone production. Mol. Cell. Endocrinol. 350, 151–162 (2012). - PMC - PubMed

[2] Hattangady N. G., Olala L. O., Bollag W. B., Rainey W. E., Acute and chronic regulation of aldosterone production. Mol. Cell. Endocrinol. 350, 151–162 (2012). - PMC - PubMed

[3] Spät A., Hunyady L., Control of aldosterone secretion: A model for convergence in cellular signaling pathways. Physiol. Rev. 84, 489–539 (2004). - PubMed

[4] Spät A., Hunyady L., Control of aldosterone secretion: A model for convergence in cellular signaling pathways. Physiol. Rev. 84, 489–539 (2004). - PubMed

[5] 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

[6] 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

[7] 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

[8] 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

[9] Nanba K., et al. ., Targeted molecular characterization of aldosterone-producing adenomas in White Americans. J. Clin. Endocrinol. Metab. 103, 3869–3876 (2018). - PMC - PubMed

[10] Nanba K., et al. ., Targeted molecular characterization of aldosterone-producing adenomas in White Americans. J. Clin. Endocrinol. Metab. 103, 3869–3876 (2018). - PMC - PubMed

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Enhanced Ca²⁺ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h^M1560V/+ )

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Enhanced Ca²⁺ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h^M1560V/+ )

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