Horm Metab Res 2017; 49(07): 520-526
DOI: 10.1055/s-0043-100935
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Expression and Histopathological Significance of Disabled-2 in Aldosterone-Producing Adenoma

Ping Li*
1   Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Min Zhang*
1   Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Jian-Qiang Ma
1   Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Qi Sun
2   Department of Pathology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Guang-Xiang Liu
3   Department of Urology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Xiao-Zhi Zhao
3   Department of Urology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Wen-Huan Feng
1   Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Shan-Mei Shen
1   Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Hong-Qian Guo
3   Department of Urology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
,
Da-Long Zhu
1   Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, P. R. China
› Author Affiliations
Further Information

Publication History

received +09 December 2016

accepted 10 January 2017

Publication Date:
17 May 2017 (online)

Abstract

The current pathological diagnosis of aldosterone-producing adenoma (APA) is challenging because no histological markers of aldosterone production are available in routine practice. A previous study demonstrated that Disabled-2 (DAB2) is a specific marker of the zona glomerulosa (ZG) in rodents. The aim of the present study was to investigate the significance of immunohistochemical staining to detect DAB2 in the adrenal tissue of patients with APA. We investigated the expression of DAB2 in 36 adrenal glands with APA, 23 adrenal glands with cortisol-producing adenoma (CPA), and 33 adrenal glands with non-functioning adenoma (NFA). Immunohistochemical staining was performed using anti-DAB2 antibodies on paraffin-embedded sections. We analysed the expression of DAB2 semi-quantitatively by scoring staining intensity, and assessed the correlation of this information with the clinical findings. DAB2 mRNA expression in adenoma tissues was evaluated by RT-PCR. DAB2 was highly expressed in the ZG in normal human adrenal glands. DAB2 expression was heterogeneous in APA, with spotted, strong staining noted in most samples (25 of 36 APA). CPA and NFA also exhibited extensive low or moderate DAB2 expression. DAB2 mRNA was significantly increased and positively correlated with CYP11B2 in APA (p<0.05). In APA, the DAB2 score adjusted for tumour volume was positively correlated with plasma aldosterone (p<0.05). Patients with low or moderate DAB2 staining more frequently exhibited high blood pressure and were diagnosed at a younger age compared with patients with high DAB2 staining. The present study clearly demonstrates that DAB2 is a specific marker of the ZG in normal human adrenal glands but that DAB2 immunostaining is not sufficiently powerful for histopathological diagnosis of APA. DAB2 might be involved in excessive aldosterone biosynthesis and correlate with specific clinical characteristics of APA patients.

* These authors contributed equally to this work


 
  • References

  • 1 Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293-2300
  • 2 Sang X, Jiang Y, Wang W, Li Y, Zhao J, Peng Y, Gu W, Chen G, Liu W, Ning G. Prevalence of and risk factors for primary aldosteronism among patients with resistant hypertension in China. J Hypertens 2013; 31: 1465-1471
  • 3 Calhoun DA. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002; 40: 892-896
  • 4 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young Jr. WF, Montori VM. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266-3281
  • 5 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
  • 6 Stowasser M, Sharman J, Leano R, Gordon RD, Ward G, Cowley D, Marwick TH. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab 2005; 90: 5070-5076
  • 7 Catena C, Colussi G, Lapenna R, Nadalini E, Chiuch A, Gianfagna P, Sechi LA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension 2007; 50: 911-918
  • 8 Nanba K, Tsuiki M, Sawai K, Mukai K, Nishimoto K, Usui T, Tagami T, Okuno H, Yamamoto T, Shimatsu A, Katabami T, Okumura A, Kawa G, Tanabe A, Naruse M. Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry. J Clin Endocrinol Metab 2013; 98: 1567-1574
  • 9 Volpe C, Höög A, Ogishima T, Mukai K, Lu M, Thorén M, Hamberger B. Immunohistochemistry improves histopathologic diagnosis in primary aldosteronism. J Clin Pathol 2013; 66: 351-354
  • 10 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
  • 11 Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE, Williams TA, Mulatero P. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol 2015; 411: 146-154
  • 12 Dekkers T, ter Meer M, Lenders JW, Hermus AR, Schultze Kool L, Langenhuijsen JF, Nishimoto K, Ogishima T, Mukai K, Azizan EA, Tops B, Deinum J, Küsters B. Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit?. J Clin Endocrinol Metab 2014; 99: E1341-E1351
  • 13 Xu XX, Yang W, Jackowski S, Rock CO. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J Biol Chem 1995; 270: 14184-14191
  • 14 Romero DG, Yanes LL, de Rodriguez AF, Plonczynski MW, Welsh BL, Reckelhoff JF, Gomez-Sanchez EP, Gomez-Sanchez CE. Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion. Endocrinology 2007; 148: 2644-2652
  • 15 Boulkroun S, Samson-Couterie B, Golib 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
  • 16 Gioco F, Seccia TM, Gomez-Sanchez EP, Rossi GP, Gomez-Sanchez CE. Adrenal histopathology in primary aldosteronism: is it time for a change?. Hypertension 2015; 66: 724-730
  • 17 Nakamura Y, Maekawa T, Felizola SJA, 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
  • 18 Zhang Z, Chen Y, Tang JJ, Xie X. Frequent loss expression of dab2 and promotor hypermethylation in human cancers: A meta-analysis and systematic review. Pak J Med Sci 2014; 30: 432-437
  • 19 Fernandes-Rosa FL, Amar L, Frédérique T, Bertherat J, Meatchi T, Zennaro MC, Boulkroun S. Functional histopathological markers of aldosterone producing adenoma and somatic KCNJ5 mutations. Mol Cell Endocrinol 2015; 408: 220-226
  • 20 Zennaro MC, Boulkroun S, Fernandes-Rosa F. An update on novel mechanisms of primary aldosteronism. J Endocrinol 2015; 224: R63-R77
  • 21 Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Pate A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Åkerström G, Wang W, Carling T. Lifton RP. K+ Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension. Science 2011; 331: 768-772
  • 22 Gomez-Sanchez CE. Primary Aldosteronism: a Channelopathy?. Hypertension 2014; 63: 668-669
  • 23 Boulkroun S, Fernandes-Rosa FL, Zennaro MC. Molecular and cellular mechanisms of aldosterone producing adenoma development. Front Endocrinol 2015; 6: 1-8
  • 24 Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH. Regulation of the Wnt signaling pathway by disabled-2 (Dab2). EMBO J 2003; 22: 3084-3094
  • 25 Steichen O, Zinzindohoué F, Plouin PF, Amar L. Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review. Horm Metab Res 2012; 44: 221-227