Specialized Center for Blood Pressure Disorders-Regione Veneto and Emergency-Hypertension Unit, Department of Medicine-DIMED, University of Padua.
Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy.
J Hypertens. 2021 Aug 1;39(8):1577-1585. doi: 10.1097/HJH.0000000000002816.
The branch of the renin--angiotensin system constituting angiotensin-(1-7) [Ang-(1-7)], the Ang II type 2 receptor, the Mas receptors and the Ang-(1-7)-forming enzyme ACE-2, by counteracting the Ang II type 1 receptor (AT1R)-mediated effects, are held to be cardiovascular protective in several conditions. However, whether Ang-(1-7) and ACE-2 are detectable in human adrenocortical tissues and whether they affect aldosterone and cortisol biosynthesis was unknown.
We measured angiotensin peptides with liquid chromatography tandem-mass spectrometry and ACE-2 mRNA with digital droplet (dd)PCR in human aldosterone-producing adenoma (APA) and APA-adjacent tissue obtained from patients with primary aldosteronism. We also investigated the effects of Ang-(1-7) and the ACE-2 activator diminazene aceturate (DIZE) on aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1) gene expression, in the absence or presence of the AT1R antagonist irbesartan, or of the MasR antagonist A779.
APA and APA-adjacent adrenocortical tissues express ACE-2 mRNA and contain detectable amounts of Ang II and Ang-(2-8), but not of Ang I, Ang-(1-5), Ang (3-8) and Ang-(1-7). Under unstimulated and Ang II- stimulated conditions Ang-(1-7) did not blunt CYP11B1 and CYP11B2 mRNA. At supraphysiological concentrations (10-4 mol/l), Ang-(1-7) stimulated both CYP11B1 and CYP11B2 mRNA via the AT1R. The ACE-2 activator DIZE increased by 1.5-fold ACE-2 mRNA but did not blunt Ang II- upregulated CYP11B1 and CYP11B2 expression.
These results do not support the hypothesis that the ACE-2/Ang-(1-7)/MasR axis play a protective role by counteracting enhanced aldosterone secretion in humans.
肾素-血管紧张素系统的分支包括血管紧张素-(1-7)[血管紧张素-(1-7)]、血管紧张素 II 型 2 受体、Mas 受体和血管紧张素-(1-7)形成酶 ACE-2，通过拮抗血管紧张素 II 型 1 受体(AT1R)介导的作用，在几种情况下被认为对心血管具有保护作用。然而，血管紧张素肽和 ACE-2 是否可在人类肾上腺组织中检测到，以及它们是否影响醛固酮和皮质醇的生物合成尚不清楚。
我们使用液相色谱串联质谱法测量了原发性醛固酮增多症患者的醛固酮产生腺瘤(APA)及其相邻组织中的血管紧张素肽，并使用数字液滴(dd)PCR 测量了 ACE-2 mRNA。我们还研究了血管紧张素-(1-7)和 ACE-2 激活剂地昔帕明(DIZE)对醛固酮合酶(CYP11B2)和 11β-羟化酶(CYP11B1)基因表达的影响，在存在或不存在 AT1R 拮抗剂依贝沙坦或 MasR 拮抗剂 A779 的情况下。
APA 和 APA 相邻的肾上腺皮质组织表达 ACE-2 mRNA，并含有可检测量的血管紧张素 II 和血管紧张素-(2-8)，但不含有血管紧张素 I、血管紧张素-(1-5)、血管紧张素(3-8)和血管紧张素-(1-7)。在未刺激和血管紧张素 II 刺激的条件下，血管紧张素-(1-7)不会使 CYP11B1 和 CYP11B2 mRNA 减弱。在生理超浓度(10-4mol/l)下，血管紧张素-(1-7)通过 AT1R 刺激 CYP11B1 和 CYP11B2 mRNA。ACE-2 激活剂 DIZE 使 ACE-2 mRNA 增加 1.5 倍，但不会使 Ang II 上调的 CYP11B1 和 CYP11B2 表达减弱。
这些结果不支持 ACE-2/血管紧张素-(1-7)/MasR 轴通过拮抗人类增强的醛固酮分泌发挥保护作用的假说。
