SAT-LB061 Sex-Specific Role of Retinoic Acid Receptor Alpha Signaling in Adrenal Cortex Development and Functional Zonation

Primary aldosteronism is the major cause of secondary arterial hypertension. Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been identified in aldosterone producing adenoma (APA). Although the role of these mutations in regulating aldosterone biosynthesis has been clearly established, the mechanisms involved in proliferation and APA formation still remain to be elucidated. The aim of our study was to identify mechanisms involved in the development of APA and, in particular, to identify specific signaling pathways responsible for abnormal cell proliferation and nodule formation. To this purpose, we have performed transcriptome analysis on 48 APA and investigated correlations of gene expression with genetic, morphological and functional characteristics of the tumors. Retinoic acid receptor alpha (RARα) signaling was identified as a central molecular network involved in nodule formation. To understand the role of RARα in adrenal cortex structure and function, we have explored the adrenal phenotype of 12 and 52 weeks old Rarα knockout (Rarα(-/-)) mice. Both male and female mice were investigated. 12 weeks old Rarα(-/-) mice showed reduced zona glomerulosa thickness and disorganization of the zona fasciculata, with modifications of the extracellular matrix and vessel architecture. This was associated with alterations in Wnt signaling and VegfA expression and an increased proliferative index, as well as a reduced expression of Star, Cyp11a1 and Cyp11b1. No modification of Cyp11b2 expression and aldosterone production were observed. Adrenal cortex disorganization was still present at 52 weeks of age, but without evidence of modification of Wnt signaling and VegfA or steroidogenic gene expression. In female mice, morphological abnormalities of the zona fasciculata were also present in 12 and 52 weeks old Rarα(-/-) mice. However, even at 12 weeks, no alterations in Wnt signaling and VegfA expression were observed, suggesting that molecular abnormalities may have occurred at an earlier time point in adrenal cortex development. Our results suggest that Rarα contributes in a sex- and time- dependent manner to the normal development and functional zonation of the adrenal cortex, by modulating both Wnt and VegfA signaling. We propose a model in which a homeostatic equilibrium between retinoic acid, Wnt and Vegf signaling pathways is required for normal development of the adrenal cortex. Dysregulation of this equilibrium in adult adrenal cortex may contribute to abnormal cell proliferation and APA development, creating a propitious environment for the emergence of specific driver mutations in APA. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.