ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)
Neurocrine regulation of aldosterone secretion: The role of substance P and NK1 receptor in aldosterone-producing adenomas
Antoine-Guy Lopez 1 , Céline Duparc 2 , Sylvie Renouf 2 , Margot D’Agostino 2 , Kelly De Sousa 2 , Laurence Amar 3 , Guillaume Defortescu 4 , Gilles Manceau 5 , Jean-Christophe Sabourin 6 , Fabio Luiz Fernandes-Rosa 7 , Maria-Christina Zennaro 8 , Tchao Meatchi 9 , Gaël Nicolas 10 , Estelle Louiset 2 & Hervé Lefebvre 1,11
1Univ Rouen Normandie, Inserm, NorDiC UMR 1239, CHU Rouen, Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen, France; 2Univ Rouen Normandie, Inserm, NorDiC UMR 1239, Rouen, France; 3Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Hypertension Department, Paris, France; 4Rouen University Hospital, Department of Urology, Rouen, France; 5Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Department of Digestive Surgery, Paris, France; 6Rouen University Hospital, Department of Pathology and Inserm U1245, Rouen, France; 7Université de Paris Cité, PARCC, Inserm, Paris, France; 8Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Département de Médecine Génomique des Tumeurs et des Cancers, Fédération de Génétique et de Médecine Génomique, Paris, France; 9Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Department of Pathology, Paris, France; 10Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France; 11Rouen University Hospital, Tumor BioBank-Centre for Biological Resources, Rouen, France
JOINT226
Background: Aldosterone-producing adenoma (APA) is a major cause of primary aldosteronism (PA), the most prevalent form of secondary hypertension. While significant progress has been made in identifying somatic mutations in genes driving aldosterone secretion, the pathophysiology of PA remains partially understood. Recent studies have revealed that Substance P (SP), a neuropeptide encoded by the TAC1 gene, stimulates aldosterone production by activating the neurokinin type 1 receptor (NK1R) in the adrenal cortex. The aim of this study was to explore the expression and distribution of SP and NK1R in APA tissues and to evaluate their role in aldosterone hypersecretion.
Methods: 56 APA tissues were analyzed using quantitative RT-PCR, immunohistochemistry, and functional studies. The expression levels of TAC1 and TACR1 mRNAs were quantified to assess transcription of SP and its receptor NK1R. Immunohistochemical staining was performed to determine localization and protein expression of SP and NK1R. Functional studies were performed on primary APA cell cultures and perifused APA explants to evaluate the effects of SP on aldosterone secretion and the inhibitory potential of the NK1R antagonist aprepitant. Aldosterone pulsatility was analyzed in perifusion profiles by assessing the mean aldosterone levels, the nadir levels, the pulse frequency, the mean pulse interval, the pulse amplitude, and the integrated aldosterone secretion (area under the curve, AUC).
Results: Quantitative RT-PCR revealed significant expression levels of TAC1 and TACR1 mRNAs in APA tissues. Immunohistochemistry detected SP-positive nerve fibers in 90% of APA samples, with granular SP staining observed in a subset of adenoma cells. NK1R expression was identified in both adenoma cells and adjacent adrenal tissue with co-localization of NK1R and aldosterone synthase (CYP11B2) noted in 60% of adenomas. SP dose-dependently increased aldosterone secretion in 6 out of 10 APA cell primary cultures (ECã, …ã, € 1.7±0.3 nM; P<0.01). The NK1R antagonist aprepitant, significantly inhibited SP-induced aldosterone secretion in 3 out of 4 responsive APA samples (P<0.01). In perifusion experiments, SP administration increased the integrated aldosterone response, as measured by the area under the curve (AUC) by 153% (P<0.05).
Conclusion: These findings demonstrate that SP stimulates aldosterone production in APAs, through neurocrine and paracrine mechanisms, by activating the NK1 receptor. Targeting the SP-NK1R axis with NK1R antagonists, such as aprepitant, represents a promising therapeutic approach for a subset of patients with primary aldosteronism.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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