12425 Sexually Dimorphic Changes In Adrenocortical Cell Transdifferentiation And Activation Of Signalling Pathways In Response To Pathophysiological Stimuli

Abstract

Disclosure: N. Faedda: None. A. Abdellatif: None. B. Fedlaoui: None. M. Fayad: None. R. Chamoun: None. F. Fernandes-Rosa: None. A. Briones Alonso: None. S. Baron: None. S. Boulkroun: None. M. Zennaro: None.

Background: Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, affecting up to 25% of patients with treatment-resistant hypertension. Mutations in genes involved in aldosterone production or zona glomerulosa (zG) cell homeostasis have been linked to PA Genome-wide association studies have also identified chromosomal loci associated with increased PA risk, suggesting that genetic susceptibility may contribute to aldosterone dysregulation and PA. The adrenal cortex undergoes constant renewal from stem/progenitor cells and transdifferentiation between its three different layers. We hypothesise that dysregulated transdifferentiation may create a propitious environment for the occurrence of somatic mutations in PA. This study aims to investigate molecular mechanisms underlying transdifferentiation in response to pathophysiological stimuli. Methods: We developed and characterised a new Cyp11b2-cre mouse model in which Cre insertion does not disrupt the Cyp11b2 gene. These mice were crossed with mTmG reporter mice (Cyp11b2-Cre::mTmG), to track cell lineage conversion within the adrenal cortex. Morphological, hormonal and molecular studies were conducted on mice subjected to high or low salt diets (HSD/LSD) and dexamethasone (DXM) treatment, challenges known to modulate adrenal cortex plasticity and function. Results: Heterozygous and homozygous Cyp11b2-cre mice maintain normal aldosterone synthase (AS) expression. In Cyp11b2-Cre::mTmG mice, the zG is entirely GFP⁺ by the first two weeks of life with transdifferentiation continuing into the zona fasciculata (zF) to reach 90% GFP⁺ of adrenocortical cells at 9 weeks of age; transdifferentiation is faster in female than in male mice. HSD reduced Cyp11b2 expression and aldosterone levels, while LSD increased them and is associated with zG expansion. Salt diets did not affect transdifferentiation. DXM treatment suppressed Cyp11b1 expression, corticosterone levels and lead to zF atrophy, with full recovery after 3 weeks in both sexes. Expression of Wnt/β-catenin genes was significantly increased during DXM suppression in females but not in males. The size of the zG (Dab2⁺ cells) increased in mice of both sexes under DXM treatment, suggesting an inhibitory effect on transdifferentiation. scRNA seq data are currently being analysed to better elucidate pathways driving the observed morphological changes. Conclusion: Our results reveal sexually dimorphic changes in adrenocortical cell transdifferentiation and activation of signalling pathways in response to pathophysiological stimuli, providing new insight into the mechanisms involved in the maintenance of adrenal cortex homeostasis.

Presentation: 6/1/2024