Objective To explore the endocrine mechanisms of aldosterone-producing adenoma (APA) by using the microarray expression profiles of normal and APA samples. Methods The gene expression profile GSE8514 was downloaded from Gene Expression Omnibus database, including samples from normal adrenals (n = 5) and APAs (n = 10). The differentially expressed genes (DEGs) were identified by samr package and endocrine DEGs were obtained according to Clinical Genome Database. Then, functional enrichment analysis of screened DEGs was performed by DAVID (Database for Annotation, Visualization and Integrated Discovery). Finally, a regulatory network was constructed to screen endocrine genes related with adrenal dysfunction and pathway enrichment analysis for the constructed network was performed. Results A total of 2149 DEGs were identified including 379 up- and 1770 down-regulated genes. And 26 endocrine genes were filtered from the DEGs. Furthermore, the down-regulated DEGs are mainly related to protein kinase cascade, response to molecule of bacterial origin, response to lipopolysaccharide, cellular macromolecule catabolic process and macromolecule catabolic process, while the up-regulated DEGs are related with regulation of ion transport. The target genes of VDR (vitamin D receptor), one of the three endocrine genes differentially expressed in the regulatory network, were endocrine genes including CYP24A1 (25-hydroxyvitamin D-24-hydroxylase) and PTH (parathyroid hormone). Three pathways may be associated with APA pathogenesis including cytokine-cytokine receptor interaction, pathways in cancer and autoimmune thyroid disease. Conclusion The VDR is the most significant transcription factor and related endocrine genes might play important roles in the endocrine mechanisms of APA.
References
[1]
Mosso L, Carvajal C, González A, Barraza A, Avila F et al. (2003) Primary aldosteronism and hypertensive disease. Hypertension 42: 161-165. doi:10.1161/01.HYP.0000079505.25750.11. PubMed: 12796282.
[2]
Chan NN, Isaacs AJ (1999) Primary aldosteronism in general practice. Lancet 353: 1013; author reply: 10459937.
[3]
Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F et al. (2008) Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93: 3266-3281. doi:10.1210/jc.2008-0104. PubMed: 18552288.
[4]
Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR et al. (2004) Role for adrenal venous sampling in primary aldosteronism. Surgery 136: 1227-1235. doi:10.1016/j.surg.2004.06.051. PubMed: 15657580.
[5]
Young WF Jr. (2007) Adrenal causes of hypertension: pheochromocytoma and primary aldosteronism. Rev Endocr Metab Disord 8: 309-320. doi:10.1007/s11154-007-9055-z. PubMed: 17914676.
[6]
Mulatero P, Veglio F, Pilon C, Rabbia F, Zocchi C et al. (1998) Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 83: 2573-2575. doi:10.1210/jc.83.7.2573. PubMed: 9661646.
[7]
Amar L, Plouin PF, Steichen O (2010) Aldosterone-producing adenoma and other surgically correctable forms of primary aldosteronism. Orphanet J Rare Dis 5: 9. doi:10.1186/1750-1172-5-9. PubMed: 20482833.
[8]
Choi M, Scholl UI, Yue P, Bj?rklund P, Zhao B et al. (2011) K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331: 768-772. doi:10.1126/science.1198785. PubMed: 21311022.
[9]
Sakuma I, Suematsu S, Matsuzawa Y, Saito J, Omura M et al. (2013) Characterization of steroidogenic enzyme expression in aldosterone-producing adenoma: a comparison with various human adrenal tumors. Endocr J 60: 329-336. doi:10.1507/endocrj.EJ12-0270. PubMed: 23257735.
[10]
Wang T, Satoh F, Morimoto R, Nakamura Y, Sasano H et al. (2011) Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands. Eur J Endocrinol 164: 613-619. doi:10.1530/EJE-10-1085. PubMed: 21248073.
[11]
Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, et al. (2013) Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 45: 440-444, 444e441-442.
[12]
Boulkroun S, Golib Dzib JF, Samson-Couterie B, Rosa FL, Rickard AJ et al. (2013) KCNJ5 mutations in aldosterone producing adenoma and relationship with adrenal cortex remodeling. Mol Cell Endocrinol 371: 221-227. doi:10.1016/j.mce.2013.01.018. PubMed: 23376008.
[13]
Sackmann S, Lichtenauer U, Shapiro I, Reincke M, Beuschlein F (2011) Aldosterone producing adrenal adenomas are characterized by activation of calcium/calmodulin-dependent protein kinase (CaMK) dependent pathways. Horm Metab Res 43: 106-111. doi:10.1055/s-0030-1269899. PubMed: 21249615.
[14]
Lenzini L, Seccia TM, Aldighieri E, Belloni AS, Bernante P et al. (2007) Heterogeneity of aldosterone-producing adenomas revealed by a whole transcriptome analysis. Hypertension 50: 1106-1113. doi:10.1161/HYPERTENSIONAHA.107.100438. PubMed: 17938379.
[15]
Ye P, Mariniello B, Mantero F, Shibata H, Rainey WE (2007) G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism. J Endocrinol 195: 39-48. doi:10.1677/JOE-07-0037. PubMed: 17911395.
[16]
Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20: 307-315. doi:10.1093/bioinformatics/btg405. PubMed: 14960456.
[17]
Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98: 5116-5121. doi:10.1073/pnas.091062498. PubMed: 11309499.
[18]
Fang F, Flegler AJ, Du P, Lin S, Clevenger CV (2009) Expression of cyclophilin B is associated with malignant progression and regulation of genes implicated in the pathogenesis of breast cancer. Am J Pathol 174: 297-308. doi:10.2353/ajpath.2009.080753. PubMed: 19056847.
[19]
Fujita A, Sato JR, Demasi MA, Sogayar MC, Ferreira CE, et al. (2009) Comparing Pearson, Spearman and Hoeffding's D measure for gene expression association analysis. J Bioinform Comput Biol 7: 663-684.
[20]
Solomon BD, Nguyen AD, Bear KA, Wolfsberg TG (2013) Clinical Genomic Database. Proc Natl Acad Sci U S A. PubMed: 23696674.
[21]
Hulsegge I, Kommadath A, Smits MA (2009) Globaltest and GOEAST: two different approaches for Gene Ontology analysis. BMC Proc 3 Suppl 4: S10. doi:10.1186/1753-6561-3-s1-s10. PubMed: 19615110.
[22]
Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44-57. PubMed: 19131956.
[23]
Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE et al. (1998) Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 26: 362-367. doi:10.1093/nar/26.1.362. PubMed: 9399875.
[24]
Kolchanov NA, Ignatieva EV, Ananko EA, Podkolodnaya OA, Stepanenko IL et al. (2002) Transcription Regulatory Regions Database (TRRD): its status in 2002. Nucleic Acids Res 30: 312-317. doi:10.1093/nar/30.1.312. PubMed: 11752324.
[25]
Matys V, Fricke E, Geffers R, G?ssling E, Haubrock M et al. (2003) TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31: 374-378. doi:10.1093/nar/gkg108. PubMed: 12520026.
[26]
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT et al. (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13: 2498-2504. doi:10.1101/gr.1239303. PubMed: 14597658.
[27]
Ogata H, Goto S, Sato K, Fujibuchi W, Bono H et al. (1999) KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res 27: 29-34. doi:10.1093/nar/27.20.e29. PubMed: 9847135.
[28]
Boulkroun S, Samson-Couterie B, Golib-Dzib JF, Amar L, Plouin PF et al. (2011) Aldosterone-producing adenoma formation in the adrenal cortex involves expression of stem/progenitor cell markers. Endocrinology 152: 4753-4763. doi:10.1210/en.2011-1205. PubMed: 21971159.
[29]
Dunbar LA, Caplan MJ (2001) Ion pumps in polarized cells: sorting and regulation of the Na+, K+- and H+, K+-ATPases. J Biol Chem 276: 29617-29620. doi:10.1074/jbc.R100023200. PubMed: 11404365.
[30]
Szabó PM, Tamási V, Molnár V, Andrásfalvy M, T?mb?l Z et al. (2010) Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed. Oncogene 29: 3163-3172. doi:10.1038/onc.2010.80. PubMed: 20305693.
[31]
Pilon C, Mulatero P, Barzon L, Veglio F, Garrone C et al. (1999) Mutations in CYP11B1 gene converting 11beta-hydroxylase into an aldosterone-producing enzyme are not present in aldosterone-producing adenomas. J Clin Endocrinol Metab 84: 4228-4231. doi:10.1210/jc.84.11.4228. PubMed: 10566677.
[32]
Tanahashi H, Mune T, Takahashi Y, Isaji M, Suwa T et al. (2005) Association of Lys173Arg polymorphism with CYP11B2 expression in normal adrenal glands and aldosterone-producing adenomas. J Clin Endocrinol Metab 90: 6226-6231. doi:10.1210/jc.2005-0299. PubMed: 16118341.
[33]
Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B et al. (2012) Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab 97: E1567-E1572. doi:10.1210/jc.2011-3132. PubMed: 22628608.
[34]
Krone N, Arlt W (2009) Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 23: 181-192. doi:10.1016/j.beem.2008.10.014. PubMed: 19500762.
[35]
Santoro M, Melillo RM, Carlomagno F, Vecchio G, Fusco A (2004) Minireview: RET: normal and abnormal functions. Endocrinology 145: 5448-5451. doi:10.1210/en.2004-0922. PubMed: 15331579.
[36]
Correa P, Akerstrom G, Westin G (2002) Exclusive underexpression of vitamin D receptor exon 1f transcripts in tumors of primary hyperparathyroidism. Eur J Endocrinol 147: 671-675. doi:10.1530/eje.0.1470671. PubMed: 12444900.
de Borst MH, Vervloet MG, ter Wee PM, Navis G (2011) Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. J Am Soc Nephrol 22: 1603-1609. doi:10.1681/ASN.2010121251. PubMed: 21852584.
[39]
Roff A, Wilson RT (2008) A novel SNP in a vitamin D response element of the CYP24A1 promoter reduces protein binding, transactivation, and gene expression. J Steroid Biochem Mol Biol 112: 47-54. doi:10.1016/j.jsbmb.2008.08.009. PubMed: 18824104.
[40]
Kong J, Qiao G, Zhang Z, Liu SQ, Li YC (2008) Targeted vitamin D receptor expression in juxtaglomerular cells suppresses renin expression independent of parathyroid hormone and calcium. Kidney Int 74: 1577-1581. doi:10.1038/ki.2008.452. PubMed: 19034301.
[41]
Delarue C, Conlon JM, Remy-Jouet I, Fournier A, Vaudry H (2004) Endothelins as local activators of adrenocortical cells. J Mol Endocrinol 32: 1-7. doi:10.1677/jme.0.0320001. PubMed: 14765988.
[42]
Nishimoto K, Rainey WE, Bollag WB, Seki T (2013) Lessons from the gene expression pattern of the rat zona glomerulosa. Mol Cell Endocrinol 371: 107-113. doi:10.1016/j.mce.2012.12.023. PubMed: 23287491.
[43]
Nishimoto K, Rigsby CS, Wang T, Mukai K, Gomez-Sanchez CE et al. (2012) Transcriptome analysis reveals differentially expressed transcripts in rat adrenal zona glomerulosa and zona fasciculata. Endocrinology 153: 1755-1763. doi:10.1210/en.2011-1915. PubMed: 22374966.
[44]
Wolf G (2006) Renal injury due to renin-angiotensin-aldosterone system activation of the transforming growth factor-beta pathway. Kidney Int 70: 1914-1919. PubMed: 16985515.
[45]
Asmah BJ, Wan Nazaimoon WM, Norazmi K, Tan TT, Khalid BA (1997) Plasma renin and aldosterone in thyroid diseases. Horm Metab Res 29: 580-583. doi:10.1055/s-2007-979105. PubMed: 9479560.