Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
Biochem Biophys Res Commun. 2012 Feb 17;418(3):559-64. doi: 10.1016/j.bbrc.2012.01.070. Epub 2012 Jan 24.
Salt-sensitive hypertension is a characteristic of the metabolic syndrome. Given the links to cardiovascular events, the mechanisms underlying sodium metabolism may represent an important therapeutic target for this disorder. Angiotensin II (AII) is a key peptide underlying sodium retention. However, 5'AMP-activated protein kinase (AMPK) has also been reported to participate in the regulation of ion transport. In this study we examined the relationship between AII and AMPK on the development of hypertension in two salt-sensitive mouse models. In the first model, the mice were maintained on a high-fat diet (HFD) for 12 weeks, in order to develop features similar to the metabolic syndrome, including salt-sensitive hypertension. HFD-induced obese mice showed elevated systolic blood pressure and lower sodium excretion in response to salt loading, along with an increase in AII contents and inactivation of AMPK in the kidney, which were significantly improved by the treatment of an angiotensin II antagonist, losartan, for 2 weeks. To clarify the effects of AII, a second group of mice was infused with AII via an osmotic pump, which led to higher systolic blood pressure, and decreases in urinary sodium excretion and the expression of AMPK, in a manner similar to those observed in the HFD mice. However, treatment with an AMPK activator, metformin, improved the changes induced by the AII, suggesting that AII induced sodium retention works by acting on AMPK activity. Finally, we evaluated the changes in salt-sensitivity by performing 2-week salt loading experiments with or without metformin. AII infusion elevated blood pressure by salt loading but metformin prevented it. These findings indicate that AII suppresses AMPK activity in the kidney, leading to sodium retention and enhanced salt-sensitivity, and that AMPK activation may represent a new therapeutic target for obesity-related salt-sensitive hypertension.
盐敏感性高血压是代谢综合征的特征。鉴于与心血管事件的关联，钠代谢的机制可能代表了这种疾病的一个重要治疗靶点。血管紧张素 II（AII）是钠潴留的关键肽。然而，5'AMP 激活的蛋白激酶（AMPK）也被报道参与离子转运的调节。在这项研究中，我们研究了 AII 和 AMPK 之间的关系，以了解两种盐敏感型小鼠模型中高血压的发展。在第一个模型中，小鼠被维持在高脂肪饮食（HFD）12 周，以发展出类似于代谢综合征的特征，包括盐敏感性高血压。HFD 诱导的肥胖小鼠表现出升高的收缩压和盐负荷时的钠排泄减少，以及肾脏中 AII 含量的增加和 AMPK 的失活，这些都通过 2 周的血管紧张素 II 拮抗剂洛沙坦治疗得到显著改善。为了阐明 AII 的作用，第二组小鼠通过渗透泵输注 AII，导致收缩压升高，尿钠排泄减少，AMPK 表达降低，这与 HFD 小鼠观察到的情况相似。然而，用 AMPK 激活剂二甲双胍治疗改善了 AII 诱导的变化，表明 AII 诱导的钠潴留通过作用于 AMPK 活性起作用。最后，我们通过进行为期 2 周的盐负荷实验，评估了盐敏感性的变化，有无二甲双胍。AII 输注通过盐负荷升高血压，但二甲双胍可以预防。这些发现表明，AII 抑制肾脏中的 AMPK 活性，导致钠潴留和增强的盐敏感性，而 AMPK 激活可能成为肥胖相关盐敏感性高血压的新治疗靶点。
