Endocrinol Metab.  2019 Dec;34(4):355-366. 10.3803/EnM.2019.34.4.355.

Molecular Mechanisms of Primary Aldosteronism

• Tevosian S
• Fox SC
• Ghayee HK

• KMID: 2466254
• DOI: http://doi.org/10.3803/EnM.2019.34.4.355

Abstract

Primary aldosteronism (PA) results from excess production of mineralocorticoid hormone aldosterone by the adrenal cortex. It is normally caused either by unilateral aldosterone-producing adenoma (APA) or by bilateral aldosterone excess as a result of bilateral adrenal hyperplasia. PA is the most common cause of secondary hypertension and associated morbidity and mortality. While most cases of PA are sporadic, an important insight into this debilitating disease has been derived through investigating the familial forms of the disease that affect only a minor fraction of PA patients. The advent of gene expression profiling has shed light on the genes and intracellular signaling pathways that may play a role in the pathogenesis of these tumors. The genetic basis for several forms of familial PA has been uncovered in recent years although the list is likely to expand. Recently, the work from several laboratories provided evidence for the involvement of mammalian target of rapamycin pathway and inflammatory cytokines in APAs; however, their mechanism of action in tumor development and pathophysiology remains to be understood.

Keyword

Hyperaldosteronism; Hypertension; Mineralocorticoids

MeSH Terms

Adenoma
Adrenal Cortex
Aldosterone
Cytokines
Gene Expression Profiling
Humans
Hyperaldosteronism*
Hyperplasia
Hypertension
Mineralocorticoids
Mortality
Sirolimus
Aldosterone
Cytokines
Mineralocorticoids
Sirolimus

Figure

• 

  Fig. 1 (A) Normally, AT1 receptor (AT1R) activation induces depolarization as a result of inactivation of the potassium channel Kir3.4 and Na+K+-ATPase. This depolarization triggers influx of Ca2+ through voltage-gated Ca2+ channels (e.g., calcium channel, voltage-dependent, L type, alpha 1D subunit [Cav1.3]), and the resultant rise in intracellular Ca2+ activates the aldosterone synthase gene cytochrome P450 family 11 subfamily B member 2 (CYP11B2). Ca2+-ATPase (e.g., ATPase plasma membrane Ca2+ transporting 3 [ATP2B3]) subsequently shuttles Ca2+ outside the cell. (B) In cells harboring CYP11B1-CYP11B2 gene fusion event, increased CYP11B2 synthesis is controlled by the adrenocorticotropic hormone (ACTH) through its melanocortin receptor 2 (MCR2) receptor. (C) Germline gain of function mutations in chloride voltage-gated channel 2 (CLCN2) chloride channel promotes export of Cl− ions, depolarization of the plasma membrane, and opening of voltage-gated Ca2+ channels. (D) Potassium inwardly rectifying channel subfamily J member 5 (KCNJ5) mutations change the selectivity of the Kir3.4 allowing for Na+ influx. Increased concentration of Na+ ions causes depolarization in the absence of AT1R stimulation. (E) Mutations in calcium voltage-gated channel subunit alpha1 D/H (CACNA1D/1H) subunits increase conductance of Ca2+, (F) whereas mutations in ATP2B3 prevent removal of Ca2+ ions from the cell; both of these mutations increase intracellular Ca2+ concentration and activate CYP11B2 transcription and aldosterone synthesis. Ion channel mutations (encoded by the CLCN2, KCNJ5, CACNA1D/1H, and ATP2B3) in the adrenal glomerulosa cell are linked to excessive aldosterone production. FH2, familial hyperaldosteronism type 2; PASNA, Primary Aldosteronism with Seizures and Neurologic Abnormalities.

• 

  Fig. 2 Wnt-induced activation of Frizzled (Fzd) leads to inhibition of glycogen synthase kinase 3 (GSK3) in a ß-catenin independent way. GSK3 inhibition inactivates its substrate TSC, TSC2 (tuberous sclerosis complex 2 or tuberin). TSC2 is a tumor suppressor complex that controls mammalian target of rapamycin (mTOR) activity through the regulatory Rheb protein. In addition to Fzd, LDL receptor related protein 5/6 (LRP5/6) co-receptor and GSK3, the scaffold proteins of the canonical Wnt cascade, Dvl, and Axin, have been implicated in signal transduction. mTOR activation can in turn cause upregulation of the inflammatory pathways through nuclear factor κb (NF-κb) and increased aldosterone synthesis through yet unknown mechanism. GDP, guanosine-5′-triphosphate; mTORC1, mammalian target of rapamycin complex 1; GTP, guanosine-5′-diphosphate; IL, interleukin; TNF, tumor necrosis factor.

Reference

1. Logan AG. Hypertension in aging patients. Expert Rev Cardiovasc Ther. 2011; 9:113–120.

2. SPRINT Research Group. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103–2116.

3. Achelrod D, Wenzel U, Frey S. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am J Hypertens. 2015; 28:355–361.

4. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol. 2018; 6:51–59.

5. Carey RM, Muntner P, Bosworth HB, Whelton PK. Prevention and control of hypertension: JACC Health Promotion Series. J Am Coll Cardiol. 2018; 72:1278–1293.

6. Puar TH, Mok Y, Debajyoti R, Khoo J, How CH, Ng AK. Secondary hypertension in adults. Singapore Med J. 2016; 57:228–232.

7. De Nicola L, Gabbai FB, Agarwal R, Chiodini P, Borrelli S, Bellizzi V, et al. Prevalence and prognostic role of resistant hypertension in chronic kidney disease patients. J Am Coll Cardiol. 2013; 61:2461–2467.

8. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008; 117:e510–e526.

9. Epstein M, Calhoun DA. The role of aldosterone in resistant hypertension: implications for pathogenesis and therapy. Curr Hypertens Rep. 2007; 9:98–105.

10. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009; 150:776–783.

11. Duprez DA. Aldosterone and the vasculature: mechanisms mediating resistant hypertension. J Clin Hypertens (Greenwich). 2007; 9:13–18.

12. Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med. 2013; 64:233–247.

13. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341:709–717.

14. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348:1309–1321.

15. Bailey MA. 11β-Hydroxysteroid dehydrogenases and hypertension in the metabolic syndrome. Curr Hypertens Rep. 2017; 19:100.

16. Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, et al. Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci U S A. 1998; 95:9424–9429.

17. Ronzaud C, Loffing J, Bleich M, Gretz N, Grone HJ, Schutz G, et al. Impairment of sodium balance in mice deficient in renal principal cell mineralocorticoid receptor. J Am Soc Nephrol. 2007; 18:1679–1687.

18. Ronzaud C, Loffing J, Gretz N, Schutz G, Berger S. Inducible renal principal cell-specific mineralocorticoid receptor gene inactivation in mice. Am J Physiol Renal Physiol. 2011; 300:F756–F760.

19. Fraccarollo D, Berger S, Galuppo P, Kneitz S, Hein L, Schutz G, et al. Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation. 2011; 123:400–408.

20. Lim HY, Muller N, Herold MJ, van den Brandt J, Reichardt HM. Glucocorticoids exert opposing effects on macrophage function dependent on their concentration. Immunology. 2007; 122:47–53.

21. McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012; 18:1429–1433.

22. Kim SK, McCurley AT, DuPont JJ, Aronovitz M, Moss ME, Stillman IE, et al. Smooth muscle cell-mineralocorticoid receptor as a mediator of cardiovascular stiffness with aging. Hypertension. 2018; 71:609–621.

23. Laursen SB, Finsen S, Marcussen N, Quaggin SE, Hansen PBL, Dimke H. Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility. PLoS One. 2018; 13:e0193032.

24. Funder JW, Mihailidou AS. Aldosterone and mineralocorticoid receptors: clinical studies and basic biology. Mol Cell Endocrinol. 2009; 301:2–6.

25. Good ME, Chiu YH, Poon IKH, Medina CB, Butcher JT, Mendu SK, et al. Pannexin 1 channels as an unexpected new target of the anti-hypertensive drug spironolactone. Circ Res. 2018; 122:606–615.

26. Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955; 45:3–17.

27. Funder JW. Primary aldosteronism: the next five years. Horm Metab Res. 2017; 49:977–983.

28. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016; 101:1889–1916.

29. Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient's cohorts and in population-based studies: a review of the current literature. Horm Metab Res. 2012; 44:157–162.

30. Douma S, Petidis K, Doumas M, Papaefthimiou P, Triantafyllou A, Kartali N, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008; 371:1921–1926.

31. Young WF Jr. Diagnosis and treatment of primary aldosteronism: practical clinical perspectives. J Intern Med. 2019; 285:126–148.

32. Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol. 2017; 69:1811–1820.

33. Blumenfeld JD, Sealey JE, Schlussel Y, Vaughan ED Jr, Sos TA, Atlas SA, et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med. 1994; 121:877–885.

34. Katabami T, Fukuda H, Tsukiyama H, Tanaka Y, Takeda Y, Kurihara I, et al. Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism. J Hypertens. 2019; 37:1513–1520.

35. Fernandes-Rosa FL, Boulkroun S, Zennaro MC. Somatic and inherited mutations in primary aldosteronism. J Mol Endocrinol. 2017; 59:R47–R63.

36. Mulatero P, Tizzani D, Viola A, Bertello C, Monticone S, Mengozzi G, et al. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms). Hypertension. 2011; 58:797–803.

37. Perez-Rivas LG, Williams TA, Reincke M. Inherited forms of primary hyperaldosteronism: new genes, new phenotypes and proposition of a new classification. Exp Clin Endocrinol Diabetes. 2019; 127:93–99.

38. Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 1966; 95:1109–1119.

39. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992; 355:262–265.

40. Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet. 1992; 2:66–74.

41. Lenders JWM, Williams TA, Reincke M, Gomez-Sanchez CE. Diagnosis of endocrine disease: 18-oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? Eur J Endocrinol. 2018; 178:R1–R9.

42. Carvajal CA, Campino C, Martinez-Aguayo A, Tichauer JE, Bancalari R, Valdivia C, et al. A new presentation of the chimeric CYP11B1/CYP11B2 gene with low prevalence of primary aldosteronism and atypical gene segregation pattern. Hypertension. 2012; 59:85–91.

43. Stowasser M, Bachmann AW, Huggard PR, Rossetti TR, Gordon RD. Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension. J Clin Endocrinol Metab. 2000; 85:3313–3318.

44. Litchfield WR, New MI, Coolidge C, Lifton RP, Dluhy RG. Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 1997; 82:3570–3573.

45. Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD. A new genetic test for familial hyperaldosteronism type I aids in the detection of curable hypertension. Biochem Biophys Res Commun. 1995; 207:565–571.

46. Quack I, Vonend O, Rump LC. Familial hyperaldosteronism I-III. Horm Metab Res. 2010; 42:424–428.

47. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL. Clinical and pathological diversity of primary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol. 1991; 18:283–286.

48. Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Primary aldosteronism: implications of a new familial variety. J Hypertens Suppl. 1991; 9:S264–S265.

49. Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clin Exp Pharmacol Physiol. 1992; 19:319–322.

50. So A, Duffy DL, Gordon RD, Jeske YW, Lin-Su K, New MI, et al. Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity. J Hypertens. 2005; 23:1477–1484.

51. Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin JP, Huggard P, et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet. 2000; 37:831–835.

52. Fallo F, Pilon C, Barzon L, Pistorello M, Sonino N, Veglio F, et al. Retention of heterozygosity at chromosome 7p22 and 11q13 in aldosterone-producing tumours of patients with familial hyperaldosteronism not remediable by glucocorticoids. J Hum Hypertens. 2004; 18:829–830.

53. Jeske YW, So A, Kelemen L, Sukor N, Willys C, Bulmer B, et al. Examination of chromosome 7p22 candidate genes RBaK, PMS2 and GNA12 in familial hyperaldosteronism type II. Clin Exp Pharmacol Physiol. 2008; 35:380–385.

54. Scholl UI, Stolting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet. 2018; 50:349–354.

55. Fernandes-Rosa FL, Daniil G, Orozco IJ, Goppner C, El Zein R, Jain V, et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet. 2018; 50:355–361.

56. Thiemann A, Grunder S, Pusch M, Jentsch TJ. A chloride channel widely expressed in epithelial and non-epithelial cells. Nature. 1992; 356:57–60.

57. Di Bella D, Pareyson D, Savoiardo M, Farina L, Ciano C, Caldarazzo S, et al. Subclinical leukodystrophy and infertility in a man with a novel homozygous CLCN2 mutation. Neurology. 2014; 83:1217–1218.

58. Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013; 12:659–668.

59. Bosl MR, Stein V, Hubner C, Zdebik AA, Jordt SE, Mukhopadhyay AK, et al. Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption. EMBO J. 2001; 20:1289–1299.

60. Korah HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res. 2015; 47:941–946.

61. Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008; 93:3117–3123.

62. Gomez-Sanchez CE, Qi X, Gomez-Sanchez EP, Sasano H, Bohlen MO, Wisgerhof M. Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3. Mol Cell Endocrinol. 2017; 439:74–80.

63. Tezuka Y, Yamazaki Y, Kitada M, Morimoto R, Kudo M, Seiji K, et al. 18-Oxocortisol synthesis in aldosterone-producing adrenocortical adenoma and significance of KCNJ5 mutation status. Hypertension. 2019; 73:1283–1290.

64. Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011; 331:768–772.

65. Velarde-Miranda C, Gomez-Sanchez EP, Gomez-Sanchez CE. Regulation of aldosterone biosynthesis by the Kir3.4 (KCNJ5) potassium channel. Clin Exp Pharmacol Physiol. 2013; 40:895–901.

66. Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE. Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. Endocrinology. 2012; 153:1774–1782.

67. Mulatero P, Monticone S, Rainey WE, Veglio F, Williams TA. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol. 2013; 9:104–112.

68. Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A. 2012; 109:2533–2538.

69. Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, et al. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension. 2012; 59:235–240.

70. Wang H, Weng C, Chen H. Positive association between KCNJ5 rs2604204 (A/C) polymorphism and plasma aldosterone levels, but also plasma renin and angiotensin I and II levels, in newly diagnosed hypertensive Chinese: a case-control study. J Hum Hypertens. 2017; 31:457–461.

71. Murthy M, Xu S, Massimo G, Wolley M, Gordon RD, Stowasser M, et al. Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism. Hypertension. 2014; 63:783–789.

72. Monticone S, Bandulik S, Stindl J, Zilbermint M, Dedov I, Mulatero P, et al. A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue. J Clin Endocrinol Metab. 2015; 100:E114–E118.

73. Zheng FF, Zhu LM, Nie AF, Li XY, Lin JR, Zhang K, et al. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension. 2015; 65:622–628.

74. Williams TA, Monticone S, Mulatero P. KCNJ5 mutations are the most frequent genetic alteration in primary aldosteronism. Hypertension. 2015; 65:507–509.

75. Adachi M, Muroya K, Asakura Y, Sugiyama K, Homma K, Hasegawa T. Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature. Horm Res Paediatr. 2014; 82:138–142.

76. Tong A, Liu G, Wang F, Jiang J, Yan Z, Zhang D, et al. A novel phenotype of familial hyperaldosteronism type III: concurrence of aldosteronism and Cushing's syndrome. J Clin Endocrinol Metab. 2016; 101:4290–4297.

77. Satoh M, Maruhashi T, Yoshida Y, Shibata H. Systematic review of the clinical outcomes of mineralocorticoid receptor antagonist treatment versus adrenalectomy in patients with primary aldosteronism. Hypertens Res. 2019; 42:817–824.

78. Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife. 2015; 4:e06315.

79. Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, et al. CACNA1H mutations are associated with different forms of primary aldosteronism. EBioMedicine. 2016; 13:225–236.

80. Steinberg KM, Yu B, Koboldt DC, Mardis ER, Pamphlett R. Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS. Sci Rep. 2015; 5:9124.

81. Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT. CACNA1H mutations in autism spectrum disorders. J Biol Chem. 2006; 281:22085–22091.

82. Eckle VS, Shcheglovitov A, Vitko I, Dey D, Yap CC, Winckler B, et al. Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility. J Physiol. 2014; 592:795–809.

83. Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet. 2013; 45:1050–1054.

84. Talavera K, Nilius B. Biophysics and structure-function relationship of T-type Ca2+ channels. Cell Calcium. 2006; 40:97–114.

85. Wulczyn K, Perez-Reyes E, Nussbaum RL, Park M. Primary aldosteronism associated with a germline variant in CACNA1H. BMJ Case Rep. 2019; 12:e229031.

86. Marksteiner R, Schurr P, Berjukow S, Margreiter E, Perez-Reyes E, Hering S. Inactivation determinants in segment IIIS6 of Ca(v)3.1. J Physiol. 2001; 537:27–34.

87. Reimer EN, Walenda G, Seidel E, Scholl UI. CACNA1H (M1549V) mutant calcium channel causes autonomous aldosterone production in HAC15 cells and is inhibited by mibefradil. Endocrinology. 2016; 157:3016–3022.

88. Xie CB, Shaikh LH, Garg S, Tanriver G, Teo AE, Zhou J, et al. Regulation of aldosterone secretion by Cav1.3. Sci Rep. 2016; 6:24697.

89. Lenzini L, Prisco S, Caroccia B, Rossi GP. Saga of familial hyperaldosteronism: yet a new channel. Hypertension. 2018; 71:1010–1014.

90. Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013; 45:1055–1060.

91. Pinggera A, Mackenroth L, Rump A, Schallner J, Beleggia F, Wollnik B, et al. New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Hum Mol Genet. 2017; 26:2923–2932.

92. Pinggera A, Lieb A, Benedetti B, Lampert M, Monteleone S, Liedl KR, et al. CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Biol Psychiatry. 2015; 77:816–822.

93. Nanba K, Omata K, Gomez-Sanchez CE, Stratakis CA, Demidowich AP, Suzuki M, et al. Genetic characteristics of aldosterone-producing adenomas in blacks. Hypertension. 2019; 73:885–892.

94. Murakami M, Yoshimoto T, Nakano Y, Tsuchiya K, Minami I, Bouchi R, et al. Expression of inflammation-related genes in aldosterone-producing adenomas with KCNJ5 mutation. Biochem Biophys Res Commun. 2016; 476:614–619.

95. Wang B, Li X, Zhang X, Ma X, Chen L, Zhang Y, et al. Prevalence and characterization of somatic mutations in Chinese aldosterone-producing adenoma patients. Medicine (Baltimore). 2015; 94:e708.

96. Taguchi R, Yamada M, Nakajima Y, Satoh T, Hashimoto K, Shibusawa N, et al. Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab. 2012; 97:1311–1319.

97. Wu VC, Wang SM, Chueh SJ, Yang SY, Huang KH, Lin YH, et al. The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes. Sci Rep. 2017; 7:39121.

98. Boulkroun S, Samson-Couterie B, Golib-Dzib JF, Amar L, Plouin PF, Sibony M, et al. Aldosterone-producing adenoma formation in the adrenal cortex involves expression of stem/progenitor cell markers. Endocrinology. 2011; 152:4753–4763.

99. Berthon A, Stratakis CA. From β-catenin to ARM-repeat proteins in adrenocortical disorders. Horm Metab Res. 2014; 46:889–896.

100. Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagnere AM, et al. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 2005; 65:7622–7627.

101. Akerstrom T, Maharjan R, Sven Willenberg H, Cupisti K, Ip J, Moser A, et al. Activating mutations in CTNNB1 in aldosterone producing adenomas. Sci Rep. 2016; 6:19546.

102. Assie G, Libe R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N Engl J Med. 2013; 369:2105–2114.

103. Mulatero P, Schiavi F, Williams TA, Monticone S, Barbon G, Opocher G, et al. ARMC5 mutation analysis in patients with primary aldosteronism and bilateral adrenal lesions. J Hum Hypertens. 2016; 30:374–378.

104. Davies LA, Hu C, Guagliardo NA, Sen N, Chen X, Talley EM, et al. TASK channel deletion in mice causes primary hyperaldosteronism. Proc Natl Acad Sci U S A. 2008; 105:2203–2208.

105. Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, et al. Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO J. 2008; 27:179–187.

106. Guagliardo NA, Yao J, Hu C, Schertz EM, Tyson DA, Carey RM, et al. TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. Hypertension. 2012; 59:999–1005.

107. Penton D, Bandulik S, Schweda F, Haubs S, Tauber P, Reichold M, et al. Task3 potassium channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology. 2012; 153:4740–4748.

108. Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A. 2015; 112:E4591–E4599.

109. Su H, Gu Y, Li F, Wang Q, Huang B, Jin X, et al. The PI3K/AKT/mTOR signaling pathway is overactivated in primary aldosteronism. PLoS One. 2013; 8:e62399.

110. Swierczynska MM, Betz MJ, Colombi M, Dazert E, Jeno P, Moes S, et al. Proteomic landscape of aldosterone-producing adenoma. Hypertension. 2019; 73:469–480.

111. Trinh B, Hepprich M, Betz MJ, Burkard T, Cavelti-Weder C, Seelig E, et al. Treatment of primary aldosteronism with mTORC1 inhibitors. J Clin Endocrinol Metab. 2019; 104:4703–4714.

112. Hantel C, Ozimek A, Lira R, Ragazzon B, Jackel C, Frantsev R, et al. TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors. Mol Cell Endocrinol. 2016; 423:87–95.

113. Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inflammation, immunity, and hypertension. Hypertension. 2011; 57:132–140.

114. Path G, Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis. J Clin Endocrinol Metab. 1997; 82:2343–2349.

115. Mikhaylova IV, Kuulasmaa T, Jaaskelainen J, Voutilainen R. Tumor necrosis factor-alpha regulates steroidogenesis, apoptosis, and cell viability in the human adrenocortical cell line NCI-H295R. Endocrinology. 2007; 148:386–392.

116. Willenberg HS, Stratakis CA, Marx C, Ehrhart-Bornstein M, Chrousos GP, Bornstein SR. Aberrant interleukin-1 receptors in a cortisol-secreting adrenal adenoma causing Cushing's syndrome. N Engl J Med. 1998; 339:27–31.

117. Sethi JK, Vidal-Puig A. Wnt signalling and the control of cellular metabolism. Biochem J. 2010; 427:1–17.

118. Bonvalet JP. Regulation of sodium transport by steroid hormones. Kidney Int Suppl. 1998; 65:S49–S56.

119. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013; 45:440–444.e1-2.

120. Prada ETA, Burrello J, Reincke M, Williams TA. Old and new concepts in the molecular pathogenesis of primary aldosteronism. Hypertension. 2017; 70:875–881.

121. Zennaro MC, Boulkroun S, Fernandes-Rosa F. An update on novel mechanisms of primary aldosteronism. J Endocrinol. 2015; 224:R63–R77.