Heterogeneity of aldosterone-producing adenomas revealed by a whole transcriptome analysis.
Aldosterone-producing adenomas (APAs) are a common cause of arterial hypertension, but the underlying molecular mechanisms are unknown, although a transcriptional modulation of aldosterone synthase (CYP11B2) has been suggested. Aldosterone synthesis involves 2 main rate-limiting steps: cholesterol transport into mitochondria and CYP11B2 gene transcription. Evidence supports a role of Ca(2+)/calmodulin-dependent protein kinases (CAMKs) in the regulation of angiotensin II- and potassium-stimulated aldosterone production. CAMK-I mediates CYP11B2 transcription via cAMP response element binding protein and activating transcription factor 1 transcription factors and nuclear receptor Nur-related factor 1. CAMK-II affects cholesterol transport into mitochondria by acting on steroidogenic acute regulatory protein and/or cytoskeleton proteins. We analyzed the whole transcriptome of APAs as compared with a pool of normal human adrenocortical tissues. Based on steroidogenic enzyme gene expression profiles, we identified 2 APA subgroups: 1 featuring overexpression of CYP11B2, CAMK-I, 11-beta-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, and 21-hydroxylase and the underexpression of CAMK-IIB and the other one with an opposite profile. The low CYP11B2 group exhibited a longer known duration of hypertension and a lower rate of long-term cure. Thus, aldosterone overproduction in APAs involves complex alterations of aldosterone synthesis regulation rather than simply increased aldosterone synthase gene expression. Whether the molecular signature of APA carries prognostic information is worth further investigation.
Lenzini
Livia
L
Department of Experimental and Clinical Medicine (DMCS-Internal Medicine 4), School of Medicine, University of Padua, Padua, Italy.
Seccia
Teresa M
TM
Aldighieri
Enrico
E
Belloni
Anna S
AS
Bernante
Paolo
P
Giuliani
Luisa
L
Nussdorfer
Gastone G
GG
Pessina
Achille C
AC
Rossi
Gian Paolo
GP
D000236:Adenoma / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D017209:Apoptosis; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D016000:Cluster Analysis; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D017403:In Situ Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics
D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; C517596:CAMK1 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2