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Sci Rep. 2019 Oct 11;9(1):14677. doi: 10.1038/s41598-019-50988-2.

Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling.

Author information

1
INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France.
2
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
3
Centre National de la Recherche Scientifique (CNRS), Institut des Hautes Etudes Scientifiques, Bures sur Yvette, France.
4
Attoquant Diagnostics, Vienna, Austria.
5
Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center and University of Mississippi Medical Center, Jackson, MS, 39216, USA.
6
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension artérielle, Paris, France.
7
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génétique Fonctionnelle et Cancer; CNRS UMR7104, Illkirch, France.
8
INSERM, U1258, Illkirch, France.
9
Université de Strasbourg (UNISTRA), Illkirch Cedex, France.
10
CNRS UMR8246, NPS, Sorbone University, Paris, France.
11
INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France. maria-christina.zennaro@inserm.fr.
12
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. maria-christina.zennaro@inserm.fr.
13
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France. maria-christina.zennaro@inserm.fr.
14
INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France. sheerazed.boulkroun@inserm.fr.
15
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. sheerazed.boulkroun@inserm.fr.

Abstract

Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.

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