Lack of Suppression of Aldosterone Production Leads to Salt-Sensitive Hypertension in Female but Not Male Balb/C Mice
Lack of Suppression of Aldosterone Production Leads to Salt-Sensitive Hypertension in Female but Not Male Balb/C Mice
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DOI：
10.1161/hypertensionaha.118.11303
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发表时间：
2018-12-01
期刊：
影响因子：
8.3
通讯作者：
de Chantemele, Eric J. Belin
中科院分区：
文献类型：
--
作者：
Faulkner, Jessica L.;Harwood, Daisy;de Chantemele, Eric J. Belin
临床研究表明，盐敏感型高血压在女性中比在男性中更普遍。然而，盐敏感的动物模型主要集中在雄性动物的盐敏感机制上，因此，需要在雌性动物模型中阐明这些机制。我们之前已经证明雌性Balb/C小鼠比雄性小鼠具有更高的醛固酮合成酶表达和醛固酮产量。我们假设雌性Balb/C小鼠会出现盐敏感型血压升高。喂食4%氯化钠高盐(HS)饮食七天后，雌性小鼠的血压升高，雄性小鼠的血压没有改变。通过24小时尿液采集、钠平衡测量和盐水负荷排泄分析评估，服用HS饮食的女性在钠滞留方面没有明显增加。与男性相比，HS饮食的女性表现出较低的肾素-血管紧张素系统活性(血浆Ang II[血管紧张素II]、血浆肾素活性和ACE[血管紧张素转换酶]活性)，但盐诱导的肾上腺醛固酮合成酶表达增加，并保持了比HS男性更高的醛固酮水平。这导致雌性在HS饲料中的醛固酮/血浆肾素活性比比雄性高。高脂饮食雌性小鼠肾上腺血管紧张素原和瘦素受体的mRNA表达增加。HS仅对雌性小鼠的内皮依赖性松弛有损害作用。MR(盐皮质激素受体)抑制(依普利酮)恢复了服用HS饮食的女性的血压和内皮功能。总而言之，这些数据表明，Balb/C小鼠可能通过醛固酮MR介导的机制患上性别差异的盐敏感型高血压，该机制仅涉及雌性动物的内皮依赖性松弛受损。这项研究提出了第一个自发的性别特异性盐敏感性模型，它模仿了人类的病理。
Clinical studies indicate that salt-sensitive hypertension is more prevalent in women than in men. However, animal models of salt sensitivity have primarily focused on the mechanisms of salt sensitivity in male animals; therefore, elucidation of these mechanisms in female animal models is needed. We have previously shown that female Balb/C mice have higher aldosterone synthase expression and aldosterone production than males. We hypothesized that female Balb/C mice develop salt-sensitive increases in blood pressure. Seven-day feeding of a 4% NaCl high-salt (HS) diet increased blood pressure in female mice without altering blood pressure in males. Females on an HS diet displayed no apparent increases in sodium retention as assessed by 24-hour urine collection, sodium balance measure, and saline loading excretion analysis. Females on an HS diet exhibited lower renin-angiotensin system activity (plasma Ang II [angiotensin II], plasma renin activity, and ACE [angiotensin-converting enzyme] activity) compared with males but developed a salt-induced elevation in adrenal aldosterone synthase expression and retained higher aldosterone levels than males on HS. This resulted in a higher aldosterone/plasma renin activity ratio in females compared with males on HS feeding. Adrenal mRNA expression of angiotensinogen and leptin receptor was increased in female mice on an HS diet. HS impaired endothelium-dependent relaxation in female mice only. MR (mineralocorticoid receptor) inhibition (eplerenone) restored blood pressure and endothelial function in females on an HS diet. Collectively, these data indicate that Balb/C mice develop sex-discrepant salt-sensitive hypertension likely via aldosterone-MR-mediated mechanisms involving impaired endothelium-dependent relaxation in females only. This study presents the first model of spontaneous sex-specific salt sensitivity, which mimics the human pathology.