Control of CYP11B2/CYP11B1 Expression Ratio and Consequences for the Zonation of the Adrenal Cortex

Abstract

Access of corticotropin to glucocorticoid synthesis in adrenocortical cells is provided by the expression of the ACTH receptor (MC2R). Activation of the MC2R increases stimulatory G-protein, adenylyl cyclase, and protein kinase A (PKA) activities. Furthermore, PKA phosphorylates transcription factors that have a stimulating effect on glucocorticoid synthesis. Sensitivity of adrenocortical cells to renin/angiotensin-2 is conferred by the expression of the inhibitory G-protein-linked angiotensin-2 type 1 receptor (AT1R) that additionally associates to the phospholipase C-activating G-protein q. The AT1R is connected to the adrenal potassium sensory system and regulates calcium influx as well as phospholipase C-β (PLC-β) and thus calmodulin kinase-dependent transcription of steroidogenic enzymes. While AT1R signaling suppresses the influence of corticotropin on the generation of cyclic adenosine monophosphate, the expression of the AT1R and its associated enzyme activities are under the control of glucocorticoids. Thus, dominance of one of the two signaling pathways is dependent on two factors: the extracellular concentration of their ligands and the products of their signaling pathways. These findings are in favor of the hypothesis that the centripetal blood flow through the adrenal gland builds up a glucocorticoid gradient creating a morphogenetic field along which adrenal cortical cells adopt different functional states, leading to the typical zonation of the adrenal cortex.

Key words

aldosterone - cortisol - adrenal - corticotrophin - development

• References

• 1 Reincke M, Beuschlein F, Menig G, Hofmockel G, Arlt W, Lehmann R, Karl M, Allolio B. Localization and expression of adrenocorticotropic hormone receptor mRNA in normal and neoplastic human adrenal cortex. J Endocrinol 1998; 156: 415-423
• 2 Bassett MH, Suzuki T, Sasano H, White PC, Rainey WE. The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production. Mol Endocrinol 2004; 18: 279-290
• 3 Bassett MH, Zhang Y, Clyne C, White PC, Rainey WE. Differential regulation of aldosterone synthase and 11-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol 2002; 28: 125-135
• 4 Winnay JN, Hammer GD. Adrenocorticotropic hormone-mediated signaling cascades coordinate a cyclic pattern of steroidogenic factor 1-dependent transcriptional activation. Mol Endocrinol 2006; 20: 147-166
• 5 Wang XL, Bassett M, Zhang Y, Yin S, Clyne C, White PC, Rainey WE. Transcriptional Regulation of Human 11β-Hydroxylase (hCYP11B1). Endocrinology 2000; 141: 3587-3594
• 6 Bassett MH, Zhang Y, White PC, Rainey WE. Regulation of human aldosterone synthase and CYP11B1: comparing the role of the common CRE/Ad1 element. Endocr Res 2000; 26: 941-951
• 7 Sirianni R, Nogueira E, Bassett MH, Carr BR, Suzuki T, Pezzi V, Andò S, Rainey WE. The AP-1 family member FOS blocks transcriptional activity of the nuclear receptor steroidogenic factor 1. J Cell Sci 2010; 123: 3956-3965
• 8 Schuberth B, Fassnacht M, Beuschlein F, Zenkert S, Allolio B, Rickert M. Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms. Clin Endocrinol 2001; 54: 627-632
• 9 Hausdorff WP, Sekura RD, Aguilera G, Catt KJ. Control of aldosterone production by angiotensin II is mediated by two guanine nucleotide regulatory proteins. Endocrinology 1987; 120: 1668-1678
• 10 Sackmann S, Lichtenauer U, Shapiro I, Reincke M, Beuschlein F. Aldosterone producing adrenal adenomas are characterized by activation of calcium/calmodulin-dependent protein kinase (CaMK) dependent pathways. Horm Metab Res 2011; 43: 106-111
• 11 Edwards RM, Stack EJ. Angiotensin II inhibits glomerular adenylate cyclase via the angiotensin II receptor subtype 1 (AT1). J Pharmacol Exp Ther 1993; 266: 506-510
• 12 Shen T, Suzuki Y, Poyard M, Best-Belpomme M, Defer N, Hanoune J. Localization and differential expression of adenylyl cyclase messenger ribonucleic acids in rat adrenal gland determined by in situ hybridization. Endocrinology 1997; 138: 4591-4598
• 13 Condon JC, Pezzi V, Drummond BM, Yin S, Rainey WE. Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase. Endocrinology 2002; 143: 3651-3657
• 14 Rainey WE, Nakamura Y. Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol 2008; 108: 281-286
• 15 Rincon Garriz JM, Suarez C, Capponi AM. c-Fos mediates angiotensin II-induced aldosterone production and protein synthesis in bovine adrenal glomerulosa cells. Endocrinology 2009; 150: 1294-1302
• 16 Matthews RP, Guthrie CR, Wailes LM, Zhao X, Means AR, McKnight GS. Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB dependent gene expression. Mol Cell Biol 1994; 14: 6107-6116
• 17 Nogueira EF, Rainey WE. Regulation of Aldosterone Synthase by Activator Transcription Factor/cAMP Response Element-Binding Protein Family Members. Endocrinology 2010; 151: 1060-1070
• 18 Pascoe L, Curnow KM, Slutsker L, Rosler A, White PC. Mutations in the human aldosterone synthase (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc Natl Acad Sci USA 1992; 89: 4996-5000
• 19 Bassett MH, White PC, Rainey WE. A role for the NGFI-B family in adrenal zonation and adrenocortical disease. Endocr Res 2004; 30: 567-574
• 20 Nogueira EF, Xing Y, Morris CA, Rainey WE. Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis. J Mol Endocrinol 2009; 42: 319-330
• 21 Romero DG, Rilli S, Plonczynski MW, Yanes LL, Zhou MY, Gomez-Sanchez EP, Gomez-Sanchez CE. Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis. Physiol Genomics 2007; 30: 26-34
• 22 Inaoka Y, Yazawa T, Uesaka M, Mizutani T, Yamada K, Miyamoto K. Regulation of NGFI-B/Nur77 gene expression in the rat ovary and in leydig tumor cells MA-10. Mol Reprod Dev 2008; 75: 931-939
• 23 Hornsby PJ. Physiological and pathological effects of steroids on the function of the adrenal cortex. J Steroid Biochem 1987; 27: 1161-1171
• 24 Bogdarina IG, King PJ, Clark AJ. Characterization of the angiotensin (AT1b) receptor promoter and its regulation by glucocorticoids. J Mol Endocrinol 2009; 43: 73-80
• 25 Andoka G, Chauvin MA, Saez JM, Morera AM. Adrenocorticotropin regulates angiotensin II receptors in bovine adrenal cells in vitro. Biochem Biophys Res Commun 1984; 121: 441-447
• 26 Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 2004; 217: 67-74
• 27 Endoh A, Kristiansen SB, Casson PR, Buster JE, Hornsby PJ. The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 1996; 81: 3558-3565
• 28 Topor LS, Asai M, Dunn J, Majzoub JA. Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2. J Clin Endocrinol Metab 2011; 96: E31-E39
• 29 Quinkler M, Meyer B, Bumke-Vogt C, Grossmann C, Gruber U, Oelkers W, Diederich S, Bahr V. Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor. Eur J Endocrinol 2002; 146: 789-799
• 30 Raff H. Glucocorticoid inhibition of neurohypophysial vasopressin secretion. Am J Physiol 1987; 252: R635-R644
• 31 Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet ER, Monder C. Localisation of 11 beta-hydroxysteroid dehydrogenase – tissue specific protector of the mineralocorticoid receptor. Lancet 1988; 2: 986-989
• 32 Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988; 242: 583-585
• 33 Ehrhart-Bornstein M, Hinson JP, Bornstein SR, Scherbaum WA, Vinson GP. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998; 19: 101-143
• 34 Haase M, Willenberg HS, Bornstein SR. Update on the corticomedullary interaction in the adrenal gland. Endocr Dev 2011; 20: 28-37
• 35 Finotto S, Krieglstein K, Schober A, Deimling F, Lindner K, Brühl B, Beier K, Metz J, Garcia-Arraras JE, Roig-Lopez JL, Monaghan P, Schmid W, Cole TJ, Kellendonk C, Tronche F, Schütz G, Unsicker K. Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells. Development 1999; 126: 2935-2944
• 36 Charmandari E, Kino T, Chrousos GP. Familial/sporadic glucocorticoid resistance: clinical phenotype and molecular mechanisms. Ann N Y Acad Sci 2004; 1024: 168-181
• 37 van Rossum EFC, Lamberts SWJ. Glucocorticoid resistance syndrome: a diagnostic and therapeutic approach. Best Pract Res Clin Endocrinol Metab 2006; 20: 611-626
• 38 Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schütz G. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 1995; 9: 1608-1621
• 39 Oelkers W. Prolonged ACTH infusion suppresses aldosterone secretion in spite of high renin activity. Acta Endocrinol 1985; 108: 91-97
• 40 Späth M, Korovkin S, Antke C, Anlauf M, Willenberg HS. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. Eur J Endocrinol 2011; 164: 447-455
• 41 Gicquel C, Leblond-Francillard M, Bertagna X, Louvel A, Chapuis Y, Luton JP, Girard F, Le Bouc Y. Clonal analysis of human adrenocortical carcinomas and secreting adenomas. Clin Endocrinol 1994; 40: 465-477
• 42 Beuschlein F, Reincke M, Karl M, Travis WD, Jaursch-Hancke C, Abdelhamid S, Chrousos GP, Allolio B. Clonal composition of human adrenocortical neoplasms. Cancer Res 1994; 54: 4927-4932
• 43 Blanes A, Diaz-Cano SJ. DNA and kinetic heterogeneity during the clonal evolution of adrenocortical proliferative lesions. Hum Pathol 2006; 37: 1295-1303
• 44 Crivello JF, Hornsby PJ, Gill GN. Metyrapone and antioxidants are required to maintain aldosterone synthesis by cultured bovine adrenocortical cells. Endocrinology 1982; 111: 469-479
• 45 Vinson GP. Adrenocortical zonation and ACTH. Microsc Res Tech 2003; 61: 227-239
• 46 Kim AC, Hammer GD. Adrenocortical cells with stem/progenitor cell properties: recent advances. Mol Cell Endocrinol 2007; 265–266: 10-16
• 47 Hornsby PJ. Adrenarche: a cell biological perspective. J Endocrinol 2012; 214: 113-119
• 48 Bird IM. In the zone: understanding zona reticularis function and its transformation by adrenarche. J Endocrinol 2012; 214: 109-111
• 49 Brennan CH, Chittka A, Barker S, Vinson GP. Eph receptors and zonation in the rat adrenal cortex. J Endocrinol 2008; 198: 185-191
• 50 Paramonova I, Haase M, Mülders-Opgenoorth B, Ansurudeen-Rafi I, Bornstein SR, Papewalis C, Schinner S, Schott M, Scherbaum WA, Willenberg HS. The effects of the endothelium on adrenal steroidogenesis is mediated by proteins other than endothelin-1. Horm Metab Res 2010; 42: 840-845
• 51 Haase M, Ansurudeen I, Paramonova I, Schinner S, Schott M, Papewalis C, Scherbaum WA, Willenberg HS. Evidence for the involvement of endothelial cell products in adrenal CITED2 expression. Cell Tissue Res 2009; 336: 337-343