ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)
Activation of calcium signaling, using chemogenetic tools, leads to the development of hyperaldosteronism and adrenal remodeling in mice
Bakhta Fedlaoui 1 , Rania Hadri 1 , Nicolo Faedda 1 , May Fayad 1 , Isabelle Giscos-Douriez 1 , Chris Magnus 2 , Scott Sternson 2 , Stephanie Baron 3 , Fabio Fernandes-Rosa 1 , Maria-Christina Zennaro 1,4 & Sheerazed Boulkroun 1
1INSERM U970 – PARCC, Université Paris Cité, Paris, France; 2Howard Hughes Medical Institute & Department of Neurosciences, University of California, San Diego, USA; 3Service de Physiologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France; 4Service de Génétique, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France
JOINT3835
Primary aldosteronism (PA) is the most frequent form of secondary hypertension and is due to autonomous aldosterone production by the adrenal gland. The most frequent genetic cause of aldosterone producing adenoma (APA) are somatic mutations in the potassium channel KCNJ5. They affect the ion selectivity of the channel, with sodium influx leading to cell membrane depolarization and activation of calcium signaling, the major trigger for aldosterone biosynthesis. To investigate how KCNJ5 mutations lead to the development of APA, we developped a mouse model expressing specifically in the adrenal cortex, using a Cyp11b2-Cre mice generated in our laboratory, a chimeric ion channel receptor named α7-5HT3-R formed by the ligand binding domain of the α7 nicotinic acetylcholine receptor fused to the ion pore domain of the serotonin receptor 5HT3a. (Cyp11b2-Cre::α7-5HT3-R). The activation of the α7-5HT3-R by a selective agonist, the uPSEM-817, leads to sodium entry into the cells. In an adrenocortical cell model (H295R-S2 cells), we previously demonstrated that the expression of α7-5HT3-R leads to an increase of sodium entry into the cells, resulting in cell membrane depolarization, the opening of voltage-gated calcium channel, an increase in intracellular calcium concentration, and an upregulation of CYP11B2 expression and aldosterone biosynthesis. Additionally, we found that this sodium influx reduces cell proliferation and promote apoptosis. Moreover, RNA sequencing and steroidome analyses revealed unique profiles associated with sodium entry, with only partial overlap with changes induced by angiotensin II and potassium. These findings suggest that additional events may be required for the development of an APA with KCNJ5 mutation. In Cyp11b2-Cre::α7-5HT3-R mice, four weeks of treatment with uPSEM-817 induces, in both male and female, an increase in plasma aldosterone and 18-hydroxycorticosterone concentrations associated with an increase in Cyp11b2 expression and to a lesser extent, a disorganization of the adrenal cortex. After four weeks of treatment, we did not observe an increase in blood pressure or cardiac remodeling. Further investigations and longer treatments are ongoing to thoroughly characterize this mouse model. This mouse model, in which we can modulate calcium entry, provides a valuable tool for dissecting the mechanisms underlying APA development and assessing new therapeutic strategies.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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