{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:38:48Z","timestamp":1791013128206,"version":"4.1.0"},"reference-count":19,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T00:00:00Z","timestamp":1366675200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>To date, the available non-invasive remedies for primary aldosteronism are not satisfactory in clinical practice. The phosphoinositide 3-kinase (PI3Ks)\/protein kinase B (PKB or AKT)\/mammalian target of rapamycin (mTOR) signaling pathway is essential for tumorigenesis and metastasis in many types of human tumors, including renal cancer, adrenal carcinoma and pheochromocytoma. The possibility that this pathway is also necessary for the pathogenesis of primary aldosteronism has not yet been explored. To answer this question, we investigated the activity of the PI3K\/AKT\/mTOR signaling pathway in normal adrenal glands (NAGs), primary aldosteronism (PA) patients and NCI-H295R cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology\/Principal Findings<\/jats:title>\n                    <jats:p>\n                      Between January 2005 and December 2011, we retrospectively reviewed the records of 45 patients with PA. We compared clinical characteristics (age, gender and biochemical data) and the expression of phospho-AKT (p-AKT), phospho-mTOR (p-mTOR), phospho-S6 (p-S6) and vascular endothelial growth factor (VEGF) by immunohistochemical staining and western blotting, analyzing 30 aldosterone-producing adenomas (APAs), 15 idiopathic hyperaldosteronism (IHA) tissues and 12 NAGs following nephrectomy for renal tumors (control group). Compared with the control group, most of the PA patients presented with polydipsia, polyuria, resistant hypertension, profound hypokalemia, hyperaldosteronemia and decreased plasma renin activity. Compared with normal zona glomerulosa, the levels of p-AKT, p-mTOR, p-S6 and VEGF were significantly upregulated in APA and IHA. No significant differences were found between APA and IHA in the expression of these proteins. Additionally, positive correlations existed between the plasma aldosterone levels and the expression of p-AKT and p-mTOR.\n                      <jats:italic>In vitro<\/jats:italic>\n                      studies showed that mTOR inhibitor rapamycin could inhibit cell proliferation in NCI-H295R cells in a dose- and time-dependent manner. Furthermore, this inhibitor also decreased aldosterone secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data suggest that the PI3K\/AKT\/mTOR signaling pathway, which was overactivated in APA and IHA compared with normal zona glomerulosa, may mediate aldosterone hypersecretion and participate in the development of PA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0062399","type":"journal-article","created":{"date-parts":[[2013,4,23]],"date-time":"2013-04-23T17:50:20Z","timestamp":1366739420000},"page":"e62399","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["RETRACTED: The PI3K\/AKT\/mTOR Signaling Pathway Is Overactivated in Primary Aldosteronism"],"prefix":"10.1371","volume":"8","author":[{"given":"Hengchuan","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qidi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoxing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fukang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2013,4,23]]},"reference":[{"key":"pone.0062399-Mulatero1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.tem.2005.02.007","article-title":"Diagnosis of primary aldosteronism: from screening to subtype differentiation","volume":"16","author":"P Mulatero","year":"2005","journal-title":"Trends Endocrinol Metab"},{"key":"pone.0062399-Mulatero2","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1210\/jc.2003-031337","article-title":"Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents","volume":"89","author":"P Mulatero","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"pone.0062399-Stowasser1","first-page":"2149","article-title":"High rate of detection of primary aldosteronism, including surgically treatable forms, after \u2018non-selective\u2019 screening of hypertensive patients","volume":"21","author":"M Stowasser","year":"2003","journal-title":"J Hypertens"},{"key":"pone.0062399-Guertin1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ccr.2007.05.008","article-title":"Defining the role of mTOR in cancer","volume":"12","author":"DA Guertin","year":"2007","journal-title":"Cancer Cell"},{"key":"pone.0062399-Konings1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.2174\/156800909788166556","article-title":"The applicability of mTOR inhibition in solid tumors","volume":"9","author":"IR Konings","year":"2009","journal-title":"Curr Cancer Drug Targets"},{"key":"pone.0062399-Hanna1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1586\/14737140.8.2.283","article-title":"mTOR pathway in renal cell carcinoma","volume":"8","author":"SC Hanna","year":"2008","journal-title":"Expert Rev Anticancer Ther"},{"key":"pone.0062399-DeMartino1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1159\/000314280","article-title":"Role of the mTOR pathway in normal and tumoral adrenal cells","volume":"92","author":"MC De Martino","year":"2010","journal-title":"Neuroendocrinology"},{"key":"pone.0062399-Brizuela1","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1194\/jlr.M700291-JLR200","article-title":"Sphingosine-1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3K\/PKB and MEK\/ERK 1\/2 pathways","volume":"48","author":"L Brizuela","year":"2007","journal-title":"J Lipid Res"},{"key":"pone.0062399-Williams1","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1161\/HYPERTENSIONAHA.110.150318","article-title":"Teratocarcinoma-derived growth factor-1 is upregulated in aldosterone-producing adenomas and increases aldosterone secretion and inhibits apoptosis in vitro","volume":"55","author":"TA Williams","year":"2010","journal-title":"Hypertension"},{"key":"pone.0062399-Mulatero3","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1210\/jc.2007-2055","article-title":"Roles of clinical criteria, computed tomography scan, and adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes","volume":"93","author":"P Mulatero","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"pone.0062399-Liu1","first-page":"627","article-title":"Target-ing the phosphoinositide 3-kinase pathway in cancer","volume":"8","author":"P Liu","year":"2009","journal-title":"Nat Rev"},{"key":"pone.0062399-Kimura1","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/j.neuroscience.2009.05.025","article-title":"Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K\/Akt\/mTOR\/GCLc\/redox signaling pathway","volume":"162","author":"R Kimura","year":"2009","journal-title":"Neuroscience"},{"key":"pone.0062399-Takekoshi1","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.lfs.2003.07.036","article-title":"Expression of vascular endothelial growth factor (VEGF) and its cognate receptors in human pheochromocytomas","volume":"74","author":"K Takekoshi","year":"2004","journal-title":"Life Sci"},{"key":"pone.0062399-Rainey1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.mce.2003.12.020","article-title":"Adrenocortical cell lines","volume":"228","author":"WE Rainey","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"pone.0062399-Lichtenauer1","doi-asserted-by":"crossref","unstructured":"Lichtenauer UD, Shapiro I, Osswald A, Meurer S, Kulle A, et al. (2012) Characterization of NCI-H295R Cells as an In Vitro Model of Hyperaldosteronism. Horm Metab Res. Epub ahead of print.","DOI":"10.1055\/s-0032-1323810"},{"key":"pone.0062399-Doghman1","doi-asserted-by":"crossref","first-page":"4666","DOI":"10.1158\/0008-5472.CAN-09-3970","article-title":"Regulation of Insulin-like Growth Factor-Mammalian Target of Rapamycin Signaling by MicroRNA in Childhood Adrenocortical Tumors","volume":"70","author":"M Doghman","year":"2010","journal-title":"Cancer Res"},{"key":"pone.0062399-Mariniello1","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1530\/ERC-11-0337","article-title":"Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models","volume":"19","author":"B Mariniello","year":"2012","journal-title":"Endocr Relat Cancer"},{"key":"pone.0062399-Bakan1","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/MOL.0b013e328352dd03","article-title":"Connecting mTORC1 signaling to SREBP-1 activation","volume":"23","author":"I Bakan","year":"2012","journal-title":"Curr Opin Lipidol"},{"key":"pone.0062399-RgimbaldDumas1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.cellsig.2010.08.005","article-title":"Mammalian target of rapamycin (mTOR) phosphorylates inositol 1,4,5-trisphosphate receptor type 2 and increases its Ca(2+) release activity","volume":"23","author":"Y R\u00e9gimbald-Dumas","year":"2011","journal-title":"Cell Signal"}],"updated-by":[{"DOI":"10.1371\/journal.pone.0335779","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000}},{"DOI":"10.1371\/journal.pone.0335779","type":"retraction","label":"Retraction","source":"retraction-watch","updated":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"record-id":"69735"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0062399","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T17:09:02Z","timestamp":1762276142000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0062399"}},"subtitle":[],"editor":[{"given":"Swati Palit","family":"Deb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,4,23]]},"references-count":19,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,4,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0062399","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,4,23]]}}}