Lopez, A.-G. | Search bioRxiv

bioRxiv2025

Regulation of Aldosterone Secretion by Substance P and the NK1 Receptor in Aldosterone-Producing Adenomas

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.

physiology↗

bioRxiv2020

PKA drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

Large Cell Calcifying Sertoli Cell Tumors (LCCSCTs) are among the most frequent lesions occurring in Carney complex (CNC) male patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A leading to unrepressed PKA activity, the LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the CNC testis lesion induction. We demonstrate that Prkar1a mutation is required in both stromal and Sertoli cells for the occurrence of LCCSCT. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to understand the human LCCSCT pathogenesis and demonstrated unprecedented PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in mouse model and human CNC testes.

pathology↗