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Steroidogenesis in Aldosterone-Producing Adenoma Revisited by Transcriptome Analysis

Institut National de la Santé et de la Recherche Médicale, Unité 567, Centre National de la Recherche Scientifique 8104, University Paris 5, Cochin Institute (G.A., C.A., E.C.), 75014 Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 36, Collège de France (J.-M.G., X.J., P.C.), 75005 Paris, France; Department of Pathology, Saint Joseph Hospital (E.B., A.B.), 75014 Paris, France; Department of Cellular Biology, Commissariat à l’Energie Atomique (J.-M.E.), 91400 Saclay, France; and Department of Vascular Medicine and Arterial Hypertension, Georges Pompidou European Hospital (P.-F.P.), 75015 Paris, France

Address all correspondence and requests for reprints to: Dr. Eric Clauser, Institut National de la Santé et de la Recherche Médicale, Unité 567, Centre National de la Recherche Scientifique 8104, Université Paris 5, Endocrinology Department, Institut Cochin, 24 rue du Fg Saint Jacques, 75014 Paris, France. E-mail: clauser{at}cochin.inserm.fr.

Context: 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.

Design: 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).

Setting: The setting of this study was the Comete Network.

Patients: Patients with APA were studied.

Intervention: 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.

Outcome: 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.

Conclusion: This work provides an original and integrated view of the mechanisms of aldosterone production in PAL.

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