Horm Metab Res 2017; 49(12): 951-956
DOI: 10.1055/s-0043-122394
Review
© Georg Thieme Verlag KG Stuttgart · New York

Aldosterone-Producing Cell Clusters in Normal and Pathological States

Kei Omata
1   Department of Pathology, University of Michigan, Ann Arbor, MI, USA
2   Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan
3   Division of Clinical Hypertension, Endocrinology & Metabolism, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan
,
Scott A. Tomlins
1   Department of Pathology, University of Michigan, Ann Arbor, MI, USA
4   Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
5   Department of Urology, University of Michigan, Ann Arbor, MI, USA
6   Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
,
William E. Rainey
7   Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
8   Department of Medicine, University of Michigan, Ann Arbor, MI, USA
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Publikationsverlauf

received 28. August 2017

accepted 30. Oktober 2017

Publikationsdatum:
04. Dezember 2017 (online)

Abstract

Primary aldosteronism (PA) significantly increases the risk of cardiovascular complications, and early diagnosis and targeted treatment based on its pathophysiology is warranted. Next-generation sequencing (NGS) has revealed recurrent somatic mutations in aldosterone-driving genes in aldosterone-producing adenoma (APA). By applying CYP11B2 (aldosterone synthase) immunohistochemistry and NGS to adrenal glands from normal subjects and PA patients, we and others have shown that CYP11B2-positive cells make small clusters, termed aldosterone-producing cell clusters (APCC), beneath the adrenal capsule, and that APCC harbor somatic mutations in genes mutated in APA. We have shown that APCC are increased in CT-negative PA adrenals, while others showed potential progression from APCC to micro APA through mutations. These results suggest that APCC are a key factor for understanding the origin of PA, and further investigation on the relation between APCC and PA is highly needed.

 
  • References

  • 1 Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young Jr. WF. The management of primary aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101: 1889-1916
  • 2 Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45: 1243-1248
  • 3 Omura M, Sasano H, Fujiwara T, Yamaguchi K, Nishikawa T. Unique cases of unilateral hyperaldosteronemia due to multiple adrenocortical micronodules, which can only be detected by selective adrenal venous sampling. Metabolism 2002; 51: 350-355
  • 4 Satoh F, Morimoto R, Seiji K, Satani N, Ota H, Iwakura Y, Ono Y, Kudo M, Nezu M, Omata K, Tezuka Y, Kawasaki Y, Ishidoya S, Arai Y, Takase K, Nakamura Y, McNamara K, Sasano H, Ito S. Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism?. Eur J Endocrinol 2015; 173: 465-477
  • 5 Wu VC, Chueh SC, Chang HW, Lin WC, Liu KL, Li HY, Lin YH, Wu KD, Hsieh BS. Bilateral aldosterone-producing adenomas: Differentiation from bilateral adrenal hyperplasia. QJM 2008; 101: 13-22
  • 6 Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331: 768-772
  • 7 Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson-Couterie B, Benecke A, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 2013; 45: 440-444 444e441–442
  • 8 Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-1054
  • 9 Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 2013; 45: 1055-1060
  • 10 Kitamoto T, Suematsu S, Matsuzawa Y, Saito J, Omura M, Nishikawa T. Comparison of cardiovascular complications in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenomas. J Atheroscler Thromb 2015; 22: 191-200
  • 11 Zheng FF, Zhu LM, Nie AF, Li XY, Lin JR, Zhang K, Chen J, Zhou WL, Shen ZJ, Zhu YC, Wang JG, Zhu DL, Gao PJ. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension 2015; 65: 622-628
  • 12 Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kucukkoylu S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T. Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype. Clin Endocrinol (Oxf) 2015; 83: 779-789
  • 13 Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension 2014; 64: 354-361
  • 14 Akerstrom T, Maharjan R, Sven Willenberg H, Cupisti K, Ip J, Moser A, Stalberg P, Robinson B, Alexander Iwen K, Dralle H, Walz MK, Lehnert H, Sidhu S, Gomez-Sanchez C, Hellman P, Bjorklund P. Activating mutations in CTNNB1 in aldosterone producing adenomas. Sci Rep 2016; 6: 19546
  • 15 Hong AR, Kim JH, Song YS, Lee KE, Seo SH, Seong MW, Shin CS, Kim SW, Kim SY. Genetics of aldosterone-producing adenoma in korean patients. PLoS One 2016; 11: e0147590
  • 16 Wu VC, Huang KH, Peng KY, Tsai YC, Wu CH, Wang SM, Yang SY, Lin LY, Chang CC, Lin YH, Lin SL, Chu TS, Wu KD. Prevalence and clinical correlates of somatic mutation in aldosterone producing adenoma-Taiwanese population. Sci Rep 2015; 5: 11396
  • 17 Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV, Pezzani R, Auchus RJ, Ghayee HK, Shibata H, Kurihara I, Williams TA, Giri JG, Bollag RJ, Edwards MA, Isales CM, Rainey WE. Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab 2012; 97: E1567-E1572
  • 18 Oki K, Plonczynski MW, Lam ML, Gomez-Sanchez EP, Gomez-Sanchez CE. The potassium channel, Kir3.4 participates in angiotensin II-stimulated aldosterone production by a human adrenocortical cell line. Endocrinology 2012; 153: 4328-4335
  • 19 Gomez-Sanchez CE, Qi X, Velarde-Miranda C, Plonczynski MW, Parker CR, Rainey W, Satoh F, Maekawa T, Nakamura Y, Sasano H, Gomez-Sanchez EP. Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol 2014; 383: 111-117
  • 20 Nishimoto K, Nakagawa K, Li D, Kosaka T, Oya M, Mikami S, Shibata H, Itoh H, Mitani F, Yamazaki T, Ogishima T, Suematsu M, Mukai K. Adrenocortical zonation in humans under normal and pathological conditions. J Clin Endocrinol Metab 2010; 95: 2296-2305
  • 21 Boulkroun S, Samson-Couterie B, Dzib JF, Lefebvre H, Louiset E, Amar L, Plouin PF, Lalli E, Jeunemaitre X, Benecke A, Meatchi T, Zennaro MC. Adrenal cortex remodeling and functional zona glomerulosa hyperplasia in primary aldosteronism. Hypertension 2010; 56: 885-892
  • 22 Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, Liu CJ, Sanjanwala AR, Edwards MA, Gomez-Sanchez CE, Nanba K, Rainey WE. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA 2015; 112: E4591-E4599
  • 23 Yamazaki Y, Nakamura Y, Omata K, Ise K, Tezuka Y, Ono Y, Morimoto R, Nozawa Y, Gomez-Sanchez CE, Tomlins SA, Rainey WE, Ito S, Satoh F, Sasano H. Histopathological classification of cross-sectional image-negative hyperaldosteronism. J Clin Endocrinol Metab 2017; 102: 1182-1192
  • 24 Omata K, Anand SK, Hovelson DH, Liu C-J, Yamazaki Y, Nakamura Y, Ito S, Satoh F, Sasano H, Rainey WE, Tomlins SA. Aldosterone-producing cell clusters frequently harbor somatic mutations and accumulate with age in normal adrenals. J Endocr Soc 2017; 1: 787-799
  • 25 Nishimoto K, Seki T, Hayashi Y, Mikami S, Al-Eyd G, Nakagawa K, Morita S, Kosaka T, Oya M, Mitani F, Suematsu M, Kabe Y, Mukai K. Human adrenocortical remodeling leading to aldosterone-producing cell cluster generation. Int J Endocrinol 2016; 7834356
  • 26 Nanba K, Vaidya A, Williams GH, Zheng I, Else T, Rainey WE. Age-related autonomous aldosteronism. Circulation 2017; 136: 347-355
  • 27 Xie CB, Shaikh LH, Garg S, Tanriver G, Teo AE, Zhou J, Maniero C, Zhao W, Kang S, Silverman RB, Azizan EA, Brown MJ. Regulation of aldosterone secretion by Cav1.3. Sci Rep 2016; 6: 24697
  • 28 Nishimoto K, Seki T, Kurihara I, Yokota K, Omura M, Nishikawa T, Shibata H, Kosaka T, Oya M, Suematsu M, Mukai K. Case report: Nodule development from subcapsular aldosterone-producing cell clusters causes hyperaldosteronism. J Clin Endocrinol Metab 2016; 101: 6-9
  • 29 Nakamura Y, Maekawa T, Felizola SJ, Satoh F, Qi X, Velarde-Miranda C, Plonczynski MW, Ise K, Kikuchi K, Rainey WE, Gomez-Sanchez EP, Gomez-Sanchez CE, Sasano H. Adrenal CYP11B1/2 expression in primary aldosteronism: Immunohistochemical analysis using novel monoclonal antibodies. Mol Cell Endocrinol 2014; 392: 73-79