Role of Mast Cells in the Control of Aldosterone Secretion

Abstract

Mast cells are immune cells present in adrenals from various species. Proliferation and activation of adrenal mast cells seem to be influenced by environment, since they increase during summer and in response to sodium restriction in frogs and mouse, respectively. Although the physiological factors regulating adrenal mast cell activity have not been identified, they might involve neurotransmitters and the renin-angiotensin system. Some data indicate that adrenal mast cells stimulate proliferation of steroidogenic cells in the zona glomerulosa and activate the mineralocorticoid production. In human, mast cell degranulation stimulates aldosterone synthesis through the release of serotonin (5-HT) and activation of 5-HT4 receptors. Increase in mast cell population and upregulation of the 5-HT signaling pathway occur in aldosterone-producing adenomas. In particular, aldosterone-producing adenoma cells overexpress 5-HT4 receptors and are hyper-responsive to 5-HT4 receptor agonists. These data suggest that the intra-adrenal serotonergic regulatory system represents a potential target for development of both adrenal imaging methods to evaluate the lateralization of aldosterone production, and pharmacological treatments of primary aldosteronism.

Key words

adrenal cortex - aldosterone - aldosterone-producing adenoma - mast cells - serotonin

^§ H.L. and E.L. share senior authorship

Publication History

Received: 20 December 2019

Accepted: 05 February 2020

Article published online:
25 March 2020

• References

• 1 Bollag WB. Regulation of aldosterone synthesis and secretion. Compr Physiol 2014; 4: 1017-1055
• 2 Staessen J, Lijnen P, Fagard R. et al. Rise of plasma aldosterone during long-term captopril treatment. N Engl J Med 1981; 304: 1110
• 3 Bomback AS, Rekhtman Y, Klemmer PJ. et al. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren+valsartan) therapy. J Am Soc Hypertens JASH 2012; 6: 338-345
• 4 Schjoedt KJ, Andersen S, Rossing P. et al. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004; 47: 1936-1939
• 5 Briet M, Schiffrin EL. Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol 2010; 6: 261-273
• 6 Pitt B, Zannad F, Remme WJ. 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
• 7 Zannad F, McMurray JJV, Krum H. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364: 11-21
• 8 Sato A, Saruta T. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 2001; 29: 13-21
• 9 Ehrhart-Bornstein M, Hinson JP, Bornstein SR. et al. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998; 19: 101-143
• 10 Lefebvre H, Prévost G, Louiset E. Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism. Eur J Endocrinol 2013; 169: R115-R138
• 11 Nussdorfer GG, Mazzocchi G. Immune-endocrine interactions in the mammalian adrenal gland: Facts and hypotheses. Int Rev Cytol 1998; 183: 143-184
• 12 Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med 2015; 373: 163-172
• 13 Shamloo A, Manchandia M, Ferreira M. et al. Complex chemoattractive and chemorepellent Kit signals revealed by direct imaging of murine mast cells in microfluidic gradient chambers. Integr Biol Camb 2013; 5: 1076-1085
• 14 Veerappan A, Reid AC, Estephan R. et al. Mast cell renin and a local renin-angiotensin system in the airway: Role in bronchoconstriction. Proc Natl Acad Sci USA 2008; 105: 1315-1320
• 15 Gilfillan AM, Austin SJ, Metcalfe DD. Mast cell biology: Introduction and overview. Adv Exp Med Biol 2011; 716: 2-12
• 16 de Souza Junior DA, Santana AC, da Silva EZM. et al. The role of mast cell specific chymases and tryptases in tumor angiogenesis. BioMed Res Int 2015; 2015: 142359
• 17 Theoharides TC. Neuroendocrinology of mast cells: Challenges and controversies. Exp Dermatol 2017; 26: 751-759
• 18 Shi G-P, Bot I, Kovanen PT. Mast cells in human and experimental cardiometabolic diseases. Nat Rev Cardiol 2015; 12: 643-658
• 19 Martino L, Masini M, Bugliani M. et al. Mast cells infiltrate pancreatic islets in human type 1 diabetes. Diabetologia 2015; 58: 2554-2562
• 20 Stilling H. Zur Anatomie der Nebennieren. Arch Mikr Anat 1898; 52: 176-195
• 21 Volk TL. Morphologic observations on the summer cell of Stilling in the interrenal gland of the American bullfrog (Rana catesbeiana). Z Zellforsch Mikrosk Anat 1972; 130: 1-11
• 22 Kawamura K. Occurrence and release of histamine-containing granules in summer cells in adrenal glands of the frog Rana catesbeiana. J Anat 1986; 148: 111-119
• 23 Regueira E, Scaia MF, Volonteri MC. et al. Anteroposterior variation of the cell types in the interrenal gland of the male toad Rhinella arenarum (Amphibia, Anura). J Morphol 2013; 274: 331-343
• 24 Accordi F, Cianfoni P. Histology and ultrastructure of the adrenal gland of Rhacophorus leucomystax (Amphibia, Anura). Bull Zool 1981; 48: 277-284
• 25 Hinson JP, Vinson GP, Pudney J. et al. Adrenal mast cells modulate vascular and secretory responses in the intact adrenal gland of the rat. J Endocrinol 1989; 121: 253-260
• 26 Panula P, Kaartinen M, Mäcklin M. et al. Histamine-containing peripheral neuronal and endocrine systems. J Histochem Cytochem 1985; 33: 933-941
• 27 Boyer H-G, Wils J, Renouf S. et al. Dysregulation of aldosterone secretion in mast cell-deficient mice. Hypertension 2017; 70: 1256-1263
• 28 Lefebvre H, Contesse V, Delarue C. et al. Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype. Neuroscience 1992; 47: 999-1007
• 29 Duparc C, Moreau L, Dzib JFG. et al. Mast cell hyperplasia is associated with aldosterone hypersecretion in a subset of aldosterone-producing adenomas. J Clin Endocrinol Metab 2015; 100: E550-E560
• 30 Zhang DX, Gauthier KM, Campbell WB. Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries. Am J Physiol Endocrinol Metab 2005; 289: E1058-E1063
• 31 Scheer BT, Wise PT. Changes in the Stilling cells of frog interrenals after hypophysectomy and exposure to hypertonic saline solution. Gen Comp Endocrinol 1969; 13: 474-477
• 32 Kim JS, Kubota H, Kiuchi Y. et al. Subcapsular cell hyperplasia and mast cell infiltration in the adrenal cortex of mice: comparative study in 7 inbred strains. Exp Anim 1997; 46: 303-306
• 33 Naccache A, Louiset E, Duparc C. et al. Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal. Mol Cell Endocrinol 2016; 434: 69-80
• 34 Hinson JP, Vinson GP, Kapas S. et al. The relationship between adrenal vascular events and steroid secretion: the role of mast cells and endothelin. J Steroid Biochem Mol Biol 1991; 40: 381-389
• 35 Carvalho RF, Ribeiro RA, Falcão RA. et al. Angiotensin II potentiates inflammatory edema in rats: Role of mast cell degranulation. Eur J Pharmacol 2006; 540: 175-182
• 36 Nakamura M. The seasonal variations in the adrenal cortex cells of bullfrog, with special remark to the origination of the summer cell. Endocrinol Jpn 1967; 14: 43-59
• 37 Nogueira EF, Bollag WB, Rainey WE. Angiotensin II regulation of adrenocortical gene transcription. Mol Cell Endocrinol 2009; 302: 230-236
• 38 Mazzuco TL, Chabre O, Feige J-J. et al. Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing’s syndrome features. J Clin Endocrinol Metab 2006; 91: 196-203
• 39 Kanikowska D, Sugenoya J, Sato M. et al. Influence of season on plasma antidiuretic hormone, angiotensin II, aldosterone and plasma renin activity in young volunteers. Int J Biometeorol 2010; 54: 243-248
• 40 Lefebvre H, Compagnon P, Contesse V. et al. Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT. J Clin Endocrinol Metab 2001; 86: 5001-5007
• 41 Aikawa T, Hirose T, Matsumoto I. et al. Direct stimulatory effect of histamine on aldosterone secretion of the perfused dog adrenal gland. Jpn J Physiol 1981; 31: 457-463
• 42 Szabó PM, Wiener Z, Tömböl Z. et al. Differences in the expression of histamine-related genes and proteins in normal human adrenal cortex and adrenocortical tumors. Virchows Arch Int J Pathol 2009; 455: 133-142
• 43 Orsó E, Szalay KS, Tóth IE. et al. Effect of histamine on corticosteroid secretion of isolated human and rat adrenocortical cells. Inflamm Res 1995; 44 (Suppl. 01) S48-S49
• 44 Pagotto RM, Pereyra EN, Monzón C. et al. Histamine inhibits adrenocortical cell proliferation but does not affect steroidogenesis. J Endocrinol 2014; 221: 15-28
• 45 Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: 575-586
• 46 Aldi S, Robador PA, Tomita K. et al. IgE receptor-mediated mast-cell renin release. Am J Pathol 2014; 184: 376-381
• 47 Bram Z, Louiset E, Ragazzon B. et al. PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease. J Clin Investig. Insight 2016; 1: e87958
• 48 Contesse V, Lefebvre H, Lenglet S. et al. Role of 5-HT in the regulation of the brain-pituitary-adrenal axis: Effects of 5-HT on adrenocortical cells. Can J Physiol Pharmacol 2000; 78: 967-983
• 49 Contesse V, Lenglet S, Grumolato L. et al. Pharmacological and molecular characterization of 5-hydroxytryptamine(7) receptors in the rat adrenal gland. Mol Pharmacol 1999; 56: 552-561
• 50 Lefebvre H, Contesse V, Delarue C. et al. Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from the human adrenal cortex: In vivo and in vitro studies. J Clin Endocrinol Metab 1993; 77: 1662-1666
• 51 Le Mestre J, Duparc C, Reznik Y. et al. Illicit upregulation of serotonin signaling pathway in adrenals of patients with high plasma or intraadrenal ACTH levels. J Clin Endocrinol Metab 2019; 104: 4967-4980
• 52 Cartier D, Jégou S, Parmentier F. et al. Expression profile of serotonin4 (5-HT4) receptors in adrenocortical aldosterone-producing adenomas. Eur J Endocrinol 2005; 153: 939-947
• 53 Edwards CR, Al-Dujaili EA, Boscaro M. et al. In vivo and in vitro studies on the effect of metoclopramide on aldosterone secretion. Clin Endocrinol (Oxf) 1980; 13: 45-50
• 54 Pratt JH, Ganguly A, Parkinson CA. et al. Stimulation of aldosterone secretion by metoclopramide in humans: Apparent independence of renal and pituitary mediation. Metabolism 1981; 30: 129-134
• 55 Lefebvre H, Dhib M, Godin M. et al. Effect of the serotonin 5-HT4 receptor agonist cisapride on aldosterone secretion in corticotropic insufficiency and primary hyperaldosteronism. Neuroendocrinology 1997; 66: 229-233
• 56 Ahmed AH, Calvird M, Gordon RD. et al. Effects of two selective serotonin reuptake inhibitor antidepressants, sertraline and escitalopram, on aldosterone/renin ratio in normotensive depressed male patients. J Clin Endocrinol Metab 2011; 96: 1039-1045
• 57 Contesse V, Hamel C, Lefebvre H. et al. Activation of 5-hydroxytryptamine4 receptors causes calcium influx in adrenocortical cells: involvement of calcium in 5-hydroxytryptamine-induced steroid secretion. Mol Pharmacol 1996; 49: 481-493
• 58 Lenglet S, Louiset E, Delarue C. et al. Activation of 5-HT(7) receptor in rat glomerulosa cells is associated with an increase in adenylyl cyclase activity and calcium influx through T-type calcium channels. Endocrinology 2002; 143: 1748-1760
• 59 Louiset E, Duparc C, Lenglet S. et al. Role of cAMP/PKA pathway and T-type calcium channels in the mechanism of action of serotonin in human adrenocortical cells. Mol Cell Endocrinol 2017; 441: 99-107
• 60 Yabut JM, Desjardins EM, Chan EJ. et al. Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance. Nat Commun 2020; 11: 463
• 61 Seitz BM, Demireva EY, Xie H. et al. 5-HT does not lower blood pressure in the 5-HT7 knockout rat. Physiol Genomics 2019; 51: 302-310
• 62 Bharucha AE, Camilleri M, Haydock S. et al. Effects of a serotonin 5-HT(4) receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans. Gut 2000; 47: 667-674
• 63 Smriga M, Torii K. L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats. Proc Natl Acad Sci USA 2003; 100: 15370-15375
• 64 Duparc C, André C, Ménard J. et al. l-Lysine acts as a serotonin type 4 receptor antagonist to counteract in vitro and in vivo the stimulatory effect of serotonergic agents on aldosterone secretion in man. Horm Metab Res 2017; 49: 269-275
• 65 Lesouhaitier O, Feuilloley M, Lihrmann I. et al. Localization of diazepam-binding inhibitor-related peptides and peripheral type benzodiazepine receptors in the frog adrenal gland. Cell Tissue Res 1996; 283: 403-412
• 66 Lesouhaitier O, Feuilloley M, Vaudry H. Effect of the triakontatetraneuropeptide (TTN) on corticosteroid secretion by the frog adrenal gland. J Mol Endocrinol 1998; 20: 45-53
• 67 Willenberg HS, Ansurudeen I, Schebesta K. et al. The endothelium secretes interleukin-6 (IL-6) and induces IL-6 and aldosterone generation by adrenocortical cells. Exp Clin Endocrinol Diabetes 2008; 116 (Suppl. 01) S70-S74
• 68 Aponte-López A, Fuentes-Pananá EM, Cortes-Muñoz D. et al. Mast cell, the neglected member of the tumor microenvironment: Role in breast cancer. J Immunol Res. 2018 2584243.
• 69 Dyduch G, Kaczmarczyk K, Okoń K. Mast cells and cancer: Enemies or allies?. Pol J Pathol 2012; 63: 1-7
• 70 Strouch MJ, Cheon EC, Salabat MR. et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin Cancer Res 2010; 16: 2257-2265
• 71 Mao Y, Feng Q, Zheng P. et al. Low tumor infiltrating mast cell density confers prognostic benefit and reflects immunoactivation in colorectal cancer. Int J Cancer 2018; 143: 2271-2280
• 72 Fu H, Zhu Y, Wang Y. et al. Tumor Infiltrating Mast Cells (TIMs) Confers a Marked Survival Advantage in Nonmetastatic Clear-Cell Renal Cell Carcinoma. Ann Surg Oncol 2017; 24: 1435-1442
• 73 Liao C-P, Booker RC, Brosseau J-P. et al. Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis. J Clin Invest 2018; 128: 2848-2861
• 74 Mukai K, Tsai M, Saito H. et al. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev 2018; 282: 121-150
• 75 Hu G, Wang S, Cheng P. Tumor-infiltrating tryptase+mast cells predict unfavorable clinical outcome in solid tumors. Int J Cancer 2018; 142: 813-821
• 76 Jachetti E, Cancila V, Rigoni A. et al. Cross-talk between myeloid-derived suppressor cells and mast cells mediates tumor-specific immunosuppression in prostate cancer. Cancer Immunol Res 2018; 6: 552-565
• 77 Białas M, Dyduch G, Szpor J. et al. Microvascular density and mast cells in benign and malignant pheochromocytomas. Pol J Pathol 2012; 63: 235-242
• 78 Visciano C, Prevete N, Liotti F. et al. Tumor-associated mast cells in thyroid cancer. Int J Endocrinol 2015; 2015: 705169
• 79 Ammendola M, Gadaleta CD, Frampton AE. et al. The density of mast cells c-Kit+and tryptase+correlates with each other and with angiogenesis in pancreatic cancer patients. Oncotarget 2017; 8: 70463-70471
• 80 Aiba M, Iri H, Suzuki H. et al. Numerous mast cells in an 11-deoxycorticosterone-producing adrenocortical tumor. Histologic evaluation of benignancy and comparison with mast cell distribution in adrenal glands and neoplastic counterparts of 67 surgical specimens. Arch Pathol Lab Med 1985; 109: 357-360
• 81 Marichal T, Tsai M, Galli SJ. Mast cells: potential positive and negative roles in tumor biology. Cancer Immunol Res 2013; 1: 269-279
• 82 Boulkroun S, Samson-Couterie B, Dzib J-FG. et al. Adrenal cortex remodeling and functional zona glomerulosa hyperplasia in primary aldosteronism. Hypertension 2010; 56: 885-892
• 83 Zennaro M-C, Boulkroun S, Fernandes-Rosa F. Genetic causes of functional adrenocortical adenomas. Endocr Rev 2017; 38: 516-537
• 84 Nanba K, Omata K, Gomez-Sanchez CE. et al. Genetic characteristics of aldosterone-producing adenomas in blacks. Hypertension 2019; 73: 885-892
• 85 Liu W, Shimada M, Xiao J. et al. Nifedipine inhibits the activation of inflammatory and immune reactions in viral myocarditis. Life Sci 2009; 85: 235-240
• 86 Schjerning J, Uhrenholt TR, Svenningsen P. et al. Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse. Am J Physiol Heart Circ Physiol 2013; 304: H1094-H1102
• 87 Xiao J, Shimada M, Liu W. et al. Anti-inflammatory effects of eplerenone on viral myocarditis. Eur J Heart Fail 2009; 11: 349-353
• 88 Lefebvre H, Cartier D, Duparc C. et al. Characterization of serotonin(4) receptors in adrenocortical aldosterone-producing adenomas: in vivo and in vitro studies. J Clin Endocrinol Metab 2002; 87: 1211-1216
• 89 Lampron A, Bourdeau I, Oble S. et al. Regulation of aldosterone secretion by several aberrant receptors including for glucose-dependent insulinotropic peptide in a patient with an aldosteronoma. J Clin Endocrinol Metab 2009; 94: 750-756
• 90 Ye P, Mariniello B, Mantero F. et al. G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism. J Endocrinol 2007; 195: 39-48
• 91 Azizan EAB, Lam BYH, Newhouse SJ. et al. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. J Clin Endocrinol Metab 2012; 97: E819-E829
• 92 Itcho K, Oki K, Kobuke K. et al. Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma. Mol Cell Endocrinol 2018; 461: 100-104
• 93 Zwermann O, Suttmann Y, Bidlingmaier M. et al. Screening for membrane hormone receptor expression in primary aldosteronism. Eur J Endocrinol 2009; 160: 443-451
• 94 Grunenwald S, Mazzuco TL, Mermejo LM. et al. In vivo systematic screening for hormone receptors in primary aldosteronism reveals frequent aberrant hormone responsiveness. The Endocrine Society 92nd Annual Meeting; 2010: S1540
• 95 Marner L, Gillings N, Madsen K. et al. Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET. NeuroImage 2010; 50: 855-861
• 96 Tavares AAS, Caillé F, Barret O. et al. In vivo evaluation of 18F-MNI698: an 18F-labeled radiotracer for imaging of serotonin 4 receptors in brain. J Nucl Med 2014; 55: 858-864
• 97 Tavares AAS, Caillé F, Barret O. et al. Whole-body biodistribution and dosimetry estimates of a novel radiotracer for imaging of serotonin 4 receptors in brain: [¹⁸F]MNI-698. Nucl Med Biol 2014; 41: 432-439
• 98 Jolivet-Jaudet G, Inoue M, Takada K. et al. Circannual changes in plasma aldosterone levels in Bufo japonicus formosus. Gen Comp Endocrinol 1984; 53: 163-167