Lopez, A.-G.; Duparc, C.; Renouf, S.; D'Agostino, M.; De Sousa, K.; Amar, L.; Defortescu, G.; Manceau, G.; Sabourin, J.-C.; Fernandes-Rosa, F. L.; Zennaro, M.-C.; Meatchi, T.; Nicolas, G.; Louiset, E.; Lefebvre, H.

Aldosterone-producing adenoma (APA) is a major cause of primary aldosteronism (PA), the most frequent form of secondary hypertension. Although somatic mutations in ion channels within APA have been shown to activate Ca2+ signaling and drive aldosterone production, the pathophysiology of PA remains partially understood. Substance P (SP), encoded by the TAC1 gene, is a neuropeptide of the tachykinin family, known for its role in stimulating aldosterone production through activation of the neurokinin 1 receptor (NK1R) in the human adrenal cortex. The aim of our work was to investigate the presence of SP nerve fibers and the NK1 receptor in a large series of APA to assess the potential role of this neuropeptide in the pathophysiology of PA. We analyzed 56 APA tissues using molecular, immunohistochemical, and functional techniques to assess the expression of SP and NK1R and examine the action of SP on aldosterone secretion. SP-positive nerve fibers were detected in 90% of the APA tissues, appearing localized both within and around the adenomas, which also showed strong NK1R expression. Functional studies revealed that SP stimulated aldosterone secretion in 6 of 10 APA cultures. The NK1R antagonist aprepitant inhibited SP-induced aldosterone secretion in 3 of the 4 SP-responsive APA cultures on which the antagonist was tested. Additionally, in perifused APA explants, SP influenced aldosterone pulsatility, resulting in enhanced mineralocorticoid secretion. These findings suggest that the SP-NK1R signaling pathway may contribute to APA pathophysiology and represent a novel potential target for the pharmacological treatment of PA in a subset of patients.