Regulation of aldosterone secretion by substance P and the NK1 receptor in aldosterone-producing adenomas

IF 2.9 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Annales d'endocrinologie Pub Date : 2025-09-15 DOI:10.1016/j.ando.2025.101835

A.-G. Lopez Dr , C. Duparc Dr , S. Renouf Dr , M. D’Agostino Mme , L. Amar Pr , G. Manceau Pr , F.-L. Fernandes-Rosa Dr , M.-C. Zennaro Pr , G. Nicolas Pr , E. Louiset Dr , H. Lefebvre Pr

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引用次数: 0

Abstract

Background

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA), the most common form of secondary hypertension. While somatic mutations have been identified in genes driving aldosterone secretion, the pathophysiology of PA remains incompletely understood. Substance P (SP), a neuropeptide encoded by the TAC1 gene, has recently been shown to stimulate aldosterone production via the neurokinin type 1 receptor (NK1R) in the adrenal cortex. This study investigated SP and NK1R expression and function in APA.

Methods

In total, 56 APA samples were analyzed by quantitative RT-PCR, immunohistochemistry, and functional assays. TAC1 and TACR1 mRNA levels were quantified, and immunostaining was used to assess the localization and protein expression of SP and NK1R. Functional studies on primary APA cell cultures and perifused explants evaluated SP-induced aldosterone secretion and the effect of the NK1R antagonist aprepitant. Pulsatility parameters included mean levels, nadir, frequency, amplitude, and area under the curve (AUC).

Results

TAC1 and TACR1 mRNAs were significantly expressed in APA tissues. SP-positive nerve fibers were detected in 90% of samples, with granular SP staining APA cells. NK1R co-localized with CYP11B2 in 60% of cases. SP dose-dependently increased aldosterone secretion in 6/10 primary cultures (EC-1.7 ± 0.3 nM; P < 0.01). Aprepitant significantly inhibited SP-induced aldosterone secretion in 3 out of 4 responsive APA samples (P < 0.01). In perifusion, SP increased integrated aldosterone response, as measured by the AUC by 153%(P < 0.05).

Conclusion

SP stimulates aldosterone production in APAs via NK1R. Targeting the SP-NK1R axis could represent a therapeutic option for selected PA patients.

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P物质和NK1受体在醛固酮产生腺瘤中对醛固酮分泌的调节

背景：醛固酮生成腺瘤（APAs）是原发性醛固酮增多症（PA）的主要病因，PA是继发性高血压最常见的形式。虽然在驱动醛固酮分泌的基因中已经发现了体细胞突变，但PA的病理生理机制仍然不完全清楚。物质P （SP）是一种由TAC1基因编码的神经肽，最近被证明可以通过肾上腺皮质的神经激肽1型受体（NK1R）刺激醛固酮的产生。本研究探讨SP和NK1R在APA中的表达及功能。方法采用定量RT-PCR、免疫组化、功能检测等方法对56份APA标本进行分析。定量测定TAC1和TACR1 mRNA水平，免疫染色法评估SP和NK1R的定位和蛋白表达。对原代APA细胞培养和周围外植体的功能研究评估了sp诱导的醛固酮分泌和NK1R拮抗剂阿瑞吡坦的作用。脉搏参数包括平均水平、最低点、频率、幅度和曲线下面积（AUC）。结果APA组织中stac1和TACR1 mrna表达显著。90%的样本中检测到SP阳性神经纤维，APA细胞呈颗粒状SP染色。60%的病例中NK1R与CYP11B2共定位。SP剂量依赖性地增加了6/10个原代培养的醛固酮分泌（EC-1.7±0.3 nM; P < 0.01）。阿瑞吡坦在4个有反应的APA样本中有3个显著抑制sp诱导的醛固酮分泌（P < 0.01）。灌注时，SP增加了综合醛固酮反应，AUC测量值为153%（P < 0.05）。结论sp通过NK1R刺激APAs中醛固酮的产生。针对SP-NK1R轴可能是特定PA患者的一种治疗选择。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annales d'endocrinologie 医学-内分泌学与代谢

CiteScore

4.40

自引率

6.50%

发文量

311

审稿时长

50 days

期刊介绍： The Annales d''Endocrinologie, mouthpiece of the French Society of Endocrinology (SFE), publishes reviews, articles and case reports coming from clinical, therapeutic and fundamental research in endocrinology and metabolic diseases. Every year, it carries a position paper by a work-group of French-language endocrinologists, on an endocrine pathology chosen by the Society''s Scientific Committee. The journal is also the organ of the Society''s annual Congress, publishing a summary of the symposia, presentations and posters. "Les Must de l''Endocrinologie" is a special booklet brought out for the Congress, with summary articles that are always very well received. And finally, we publish the high-level instructional courses delivered during the Henri-Pierre Klotz International Endocrinology Days. The Annales is a window on the world, keeping alert clinicians up to date on what is going on in diagnosis and treatment in all the areas of our specialty.