Steroidogenesis in aldosterone-producing adenoma revisited by transcriptome analysis.
BACKGROUND
Primary aldosteronism (PAL) is the most frequent cause of secondary arterial hypertension. In PAL, aldosterone production is chronic, excessive, and autonomous.


OBJECTIVE
The objective of this study was to identify the angiotensin-II independent alterations of steroidogenesis responsible for PAL.


METHODS
Genomewide gene expression was compared in two tissues differentiated for aldosterone production, both nonstimulated by circulating angiotensin II and differing in their autonomy to produce aldosterone: aldosterone-producing adenoma (APA) and its adjacent dissected zona glomerulosa (ZG).


METHODS
The setting of this study was the Comete Network.


METHODS
Patients with APA were studied.


METHODS
Transcriptome comparison was made of one APA and its adjacent ZG by serial analysis of gene expression; validation by in situ hybridization was performed for 19 genes in 11 samples.


RESULTS
The study outcome was genes differentially expressed in APA and adjacent ZG.


RESULTS
Activation of steroidogenesis in PAL is restricted to the overexpression of the enzymes producing aldosterone-specific steroids, aldosterone synthase and also 21-hydroxylase, suggesting that upstream precursor production is not limiting. Increased expression of high-density lipoprotein receptor, adrenodoxin and P450 oxidoreductase suggests that these systems provide cholesterol and electrons to the mitochondrial steroidogenic enzymes. As for acute stimulation of aldosterone production, an activation of calcium signaling is suggested by concordant overexpression of calcium-binding proteins or effectors. Calcium activation may result from an abnormal activity of G(q) protein-coupled receptors. This calcium activation may be the starting point of the other gene expression changes observed in APA. Finally, other differentially expressed genes include three genes encoding unidentified proteins.


CONCLUSIONS
This work provides an original and integrated view of the mechanisms of aldosterone production in PAL.
Assié
Guillaume
G
Institut National de la Santé et de la Recherche Médicale, Unité 567, Centre National de la Recherche Scientifique 8104, Université Paris 5, Institut Cochin, 24 rue du Fg Saint Jacques, 75014 Paris, France.
Auzan
Colette
C
Gasc
Jean-Marie
JM
Baviera
Erno
E
Balaton
André
A
Elalouf
Jean-Marc
JM
Jeunemaitre
Xavier
X
Plouin
Pierre-François
PF
Corvol
Pierre
P
Clauser
Eric
E
D000236:Adenoma / Q000378:metabolism*; D000310:Adrenal Gland Neoplasms / Q000150:complications* / Q000378:metabolism*; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D002118:Calcium / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004583:Electrons; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006929:Hyperaldosteronism / Q000209:etiology*; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013256:Steroids / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015384:Zona Glomerulosa / Q000378:metabolism
D013256:Steroids; D000450:Aldosterone; D002784:Cholesterol; D002118:Calcium