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

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El Zein, Rami | Soria, Audrey, H | Golib Dzib, Jose Felipe | Rickard, Amanda, J | Fernandes-Rosa, Fabio L. | Samson-Couterie, Benoit | Giscos-Douriez, Isabelle | Rocha, Angélique | Poglitsch, Marko | Gomez-Sanchez, Celso, E | Amar, Laurence | Ghyselinck, Norbert, B. | Benecke, Arndt | Zennaro, Maria-Christina | Boulkroun, Sheerazed

Edité par CCSD ; Nature Publishing Group -

International audience. 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. Primary aldosteronism (PA) is the most common and curable form of secondary arterial hypertension, with prevalence estimations of up to 10% of cases in referred hypertensive patients, 4% of patients in primary care 1,2 and 20% of patients with resistant hypertension 3,4. Rapid diagnosis and treatment are important to prevent severe cardiovas-cular consequences of long term aldosterone exposure, which are independent of blood pressure levels and are due

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