title: MicroRNA-24 is a novel regulator of aldosterone and cortisol production in the human adrenal cortex.
abstract: Dysregulation of aldosterone or cortisol production can predispose to hypertension, as seen in aldosterone-producing adenoma, a form of primary aldosteronism. We investigated the role of microRNA (miRNA) in their production, with particular emphasis on the CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes, which produce the enzymes responsible for the final stages of cortisol and aldosterone biosynthesis, respectively. Knockdown of Dicer1, a key enzyme in miRNA maturation, significantly altered CYP11B1 and CYP11B2 expression in a human adrenocortical cell line. Screening of nondiseased human adrenal and aldosterone-producing adenoma samples yielded reproducible but distinctive miRNA expression signatures for each tissue type, with levels of certain miRNA, including microRNA-24 (miR-24), differing significantly between the 2. Bioinformatic analysis identified putative binding sites for several miRNA, including miR-24, in the 3' untranslated region of CYP11B1 and CYP11B2 mRNAs. In vitro manipulation of miR-24 confirmed its ability to modulate CYP11B1 and CYP11B2 expression, as well as cortisol and aldosterone production. This study demonstrates that Dicer-dependent miRNA, including miR-24, can post-transcriptionally regulate expression of the CYP11B1 and CYP11B2 genes. Normal adrenal tissue and aldosterone-producing adenoma differ significantly and reproducibly in their miRNA expression profiles, with miR-24 significantly downregulated in the latter. Adrenal miRNA may, therefore, be a novel and valid target for the therapeutic manipulation of corticosteroid biosynthesis.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Stacy
authors.initials: S
authors.lastname: Robertson
authors.forename: Scott M
authors.initials: SM
authors.lastname: MacKenzie
authors.forename: Samantha
authors.initials: S
authors.lastname: Alvarez-Madrazo
authors.forename: Louise A
authors.initials: LA
authors.lastname: Diver
authors.forename: Junjun
authors.initials: J
authors.lastname: Lin
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Robert
authors.initials: R
authors.lastname: Fraser
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
authors.forename: Eleanor
authors.initials: E
authors.lastname: Davies
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000302:Adrenal Cortex / Q000201:enzymology / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D006854:Hydrocortisone
keywords: aldosterone; aldosterone synthase; cortisol; hypertension; microRNAs; steroid 11-beta-hydroxylase