Morais Rafael L, Hilzendeger Aline M, Visniauskas Bruna, Todiras Mihail, Alenina Natalia, Mori Marcelo A, Araújo Ronaldo C, Nakaie Clovis R, Chagas Jair R, Carmona Adriana K, Bader Michael, Pesquero João B
Departamento de Biofísica, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
Departamento de Psicobiologia, Universidade Federal de São Paulo, Campus São Paulo, São Paulo, Brazil.
Am J Physiol Heart Circ Physiol. 2017 Mar 1;312(3):H437-H445. doi: 10.1152/ajpheart.00485.2016. Epub 2016 Dec 9.
Obesity is assumed to be a major cause of human essential hypertension; however, the mechanisms responsible for weight-related increase in blood pressure (BP) are not fully understood. The prevalence of hypertension induced by obesity has grown over the years, and the role of the renin-angiotensin-aldosterone system (RAAS) in this process continues to be elucidated. In this scenario, the mice are a genetic obesity model generally used for metabolic disorder studies. These mice are normotensive even though they present several metabolic conditions that predispose them to hypertension. Although the normotensive trait in these mice is associated with the poor activation of sympathetic nervous system by the lack of leptin, we demonstrated that mice present massively increased aminopeptidase A (APA) activity in the circulation. APA enzyme metabolizes angiotensin (ANG) II into ANG III, a peptide associated with intrarenal angiotensin type 2 (AT) receptor activation and induction of natriuresis. In these mice, we found increased ANG-III levels in the circulation, high AT receptor expression in the kidney, and enhanced natriuresis. AT receptor blocking and APA inhibition increased BP, suggesting the ANG III-AT receptor axis as a complementary BP control mechanism. Circulating APA activity was significantly reduced by weight loss independently of leptin, indicating the role of fat tissue in APA production. Therefore, in this study we provide new data supporting the role of APA in BP control in mouse strain. These findings improve our comprehension about obesity-related hypertension and suggest new tools for its treatment. In this study, we reported an increased angiotensin III generation in the circulation of mice caused by a high aminopeptidase A activity. These findings are associated with an increased natriuresis found in these mice and support the role of renin-angiotensin-aldosterone system as additional mechanism regulating blood pressure in this genetic obese strain.
肥胖被认为是人类原发性高血压的主要原因；然而，体重相关的血压（BP）升高的机制尚未完全明确。多年来，肥胖诱发的高血压患病率一直在上升，肾素 - 血管紧张素 - 醛固酮系统（RAAS）在这一过程中的作用仍在不断阐明。在这种情况下，小鼠是一种通常用于代谢紊乱研究的遗传性肥胖模型。这些小鼠尽管存在多种易导致高血压的代谢状况，但血压正常。虽然这些小鼠的血压正常特征与因缺乏瘦素导致的交感神经系统激活不足有关，但我们证明小鼠循环中的氨肽酶A（APA）活性大幅增加。APA酶将血管紧张素（ANG）II代谢为ANG III，这是一种与肾内血管紧张素2型（AT）受体激活和利钠作用诱导相关的肽。在这些小鼠中，我们发现循环中ANG - III水平升高、肾脏中AT受体表达高以及利钠作用增强。AT受体阻断和APA抑制会使血压升高，表明ANG III - AT受体轴是一种补充性的血压控制机制。体重减轻会独立于瘦素显著降低循环中的APA活性，表明脂肪组织在APA产生中的作用。因此，在本研究中，我们提供了新的数据支持APA在小鼠品系血压控制中的作用。这些发现提高了我们对肥胖相关高血压的理解，并为其治疗提出了新的工具。在本研究中，我们报告了由于高氨肽酶A活性导致小鼠循环中血管紧张素III生成增加。这些发现与这些小鼠中发现的利钠作用增加相关，并支持肾素 - 血管紧张素 - 醛固酮系统作为调节这种遗传性肥胖品系血压的额外机制的作用。
