血管紧张素转移酶2-血管紧张素(1-7)-Mas轴在肾脏疾病发病机制中的作用

肾素-血管紧张素系统(RAS)过度兴奋,尤其是肾脏局部RAS高表达对肾脏疾病发生发展起重要作用.随着对RAS深入研究发现,除经典的RAS途径外,还有一条新的RAS途径:血管紧张素转移酶2-血管紧张素(1-7)-Mas轴[ACE2-Ang(1-7)-Mas轴],它和经典RAS相互作用,共同调节机体内环境稳定、维持肾脏功能正常.本文就ACE2-Ang(1-7)-Mas轴在肾脏生理及疾病中的作用及其机制做一简述.     

血管紧张素受体阻滞药应作为卒中一级和二级预防的一线用药吗?

对于卒中的一级和二级预防,血压仍然是单个最重要的可干预危险因素.具有里程碑意义的培哚普利保护复发性卒中研究(Perindopril Protection Against Recurrent Stroke Study,PROGRESS)试验表明,卒中后至少2周开始血管紧张素转换酶抑制药(angiotensin-converting-enzyme inhibitor,ACEI)培哚普利降压治疗,可降低复发性卒中和其他心血管事件的风险.虽然大多数系统评价提示几乎所有类型的抗高血压药预防卒中的效果相似,但也存在一些重要的例外.单用替米沙坦或与雷米普利联合应用改善总体终点指标试验(Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial,ONTARGET)证实,血管紧张素受体阻滞药(angiotensin receptor blocker,ARB)替米沙坦在预防血管病或糖尿病患者的心血管事件方面与雷米普利等效;而在相似人群中,雷米普利预防卒中相当有效.人们根据ARB对肾素-血管紧张素-醛固酮系统的调节作用推测,其有优于其他降血压药的卒中保护作用.但是,多方面的临床试验提示,ARB在卒中预防中并无独特的作用.因此,对是否应将ARB作为卒中一级和二级预防的一线用药一直存在着争论.     

血管紧张素转换酶2研究新进展

血管紧张素转换酶(ACE)是一种锌指金属蛋白酶,对肾素-血管紧张素系统(RAS)有关键调控作用.ACE 2主要分布在心脏、肾脏和睾丸,能水解血管紧张素(Ang)Ⅰ,产生Ang 1-9,还能水解RAS中的主要物质AngⅡ,产生具有血管扩张作用的Ang 1-7.研究表明ACE 2可能在RAS中扮演与ACE相反的角色,达到血管收缩和舒张之间的平衡,与高血压、心力衰竭及糖尿病肾病等关系密切.     

脑内血管紧张素Ⅱ受体亚型与高血压研究进展

肾素-血管紧张素系统(RAS)不仅作用于外周血管,而且作用于中枢神经系统,使血压升高。脑内RAS的发现对于了解局部生成肽激素的作用提供了新的概念。AngⅡ不仅是一种循环激素,而且也作为中枢神经系统的一种多肽在血压调节等方面发挥着重要作用。目前认为AngⅡ受体介导了AngⅡ在脑内的信息传递。文章就脑内AngⅡ受体亚型与高血压的研究进展作一综述。     

血管紧张素Ⅱ对胰岛细胞的作用

肾素-血管紧张素系统(RAS)包括循环RAS和局部RAS,其核心活性物质均为血管紧张素Ⅱ(AngⅡ).已证实胰岛局部存在RAS,并可不依赖于循环RAS独立合成AngⅡ.现在认为,胰岛局部RAS对胰岛细胞的内分泌功能调节起重要作用.AngⅡ和相应胞膜、胞浆内的不同AngⅡ受体结合后,通过改变血管收缩性而改变胰岛供血和局部氧张力,通过蛋白激酶通路等机制,影响胰岛素和生长抑素的分泌.但局部RAS的过度激活会使胰腺局部的活性氧簇牛成增多,导致胰岛细胞功能异常.促进胰岛细胞凋亡进程,参与胰岛局部炎性反应过程和胰腺的纤维化,同时在外周组织中介导胰岛素抵抗的产生,从而间接影响胰岛细胞功能.     

急性心肌缺血大鼠心肌组织中PAS系统的表达变化

目的 探讨急性心肌缺血大鼠心肌组织中肾素-血管紧张素系统(RAS)的表达变化.方法 通过结扎大鼠冠状动脉左前降支复制急性心肌缺血模型.采用RT-PCR方法 测定心肌组织中血管紧张素原(AGT)、血管紧张素转换酶(ACE)、血管紧张素1型受体(AT1)/血管紧张素2型受体(AT2)及水通道蛋白4(AQP4)mRNA的表达.结果 与假手术组相比,急性心肌缺血组大鼠心肌组织中AGT mRNA的变化不明显,ACE及AT1 mRNA的表达明显降低(P＜0.05),AT2 及AQP4 mRNA的表达明显升高(P＜0.05).结论 局部RAS及AQP4参与了急性心肌缺血的过程.     

血管紧张素受体阻滞药应作为卒中一级和二级预防的一线用药吗?

对于卒中的一级和二级预防,血压仍然是单个最重要的可干预危险因素.具有里程碑意义的培哚普利保护复发性卒中研究(Perindopril Protection Against Recurrent Stroke Study,PROGRESS)试验表明,卒中后至少2周开始血管紧张素转换酶抑制药(angiotensin-converting-enzyme inhibitor,ACEI)培哚普利降压治疗,可降低复发性卒中和其他心血管事件的风险.虽然大多数系统评价提示几乎所有类型的抗高血压药预防卒中的效果相似,但也存在一些重要的例外.单用替米沙坦或与雷米普利联合应用改善总体终点指标试验(Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial,ONTARGET)证实,血管紧张素受体阻滞药(angiotensin receptor blocker,ARB)替米沙坦在预防血管病或糖尿病患者的心血管事件方面与雷米普利等效;而在相似人群中,雷米普利预防卒中相当有效.人们根据ARB对肾素-血管紧张素-醛固酮系统的调节作用推测,其有优于其他降血压药的卒中保护作用.但是,多方面的临床试验提示,ARB在卒中预防中并无独特的作用.因此,对是否应将ARB作为卒中一级和二级预防的一线用药一直存在着争论.     

血管紧张素受体阻滞药应作为卒中一级和二级预防的一线用药吗?

对于卒中的一级和二级预防,血压仍然是单个最重要的可干预危险因素.具有里程碑意义的培哚普利保护复发性卒中研究(Perindopril Protection Against Recurrent Stroke Study,PROGRESS)试验表明,卒中后至少2周开始血管紧张素转换酶抑制药(angiotensin-converting-enzyme inhibitor,ACEI)培哚普利降压治疗,可降低复发性卒中和其他心血管事件的风险.虽然大多数系统评价提示几乎所有类型的抗高血压药预防卒中的效果相似,但也存在一些重要的例外.单用替米沙坦或与雷米普利联合应用改善总体终点指标试验(Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial,ONTARGET)证实,血管紧张素受体阻滞药(angiotensin receptor blocker,ARB)替米沙坦在预防血管病或糖尿病患者的心血管事件方面与雷米普利等效;而在相似人群中,雷米普利预防卒中相当有效.人们根据ARB对肾素-血管紧张素-醛固酮系统的调节作用推测,其有优于其他降血压药的卒中保护作用.但是,多方面的临床试验提示,ARB在卒中预防中并无独特的作用.因此,对是否应将ARB作为卒中一级和二级预防的一线用药一直存在着争论.     

脑肾素-血管紧张素系统在脑缺血性损伤中的作用机制

<正>随着肾素-血管紧张素(Ang)系统(RAS)的不断认识,发现脑中有着独立的RAS,且运用其阻断剂不仅在心血管疾病中取得了较满意的效果,甚至发现在脑缺血性损伤及其他脑功能退化性疾病中有着巨大潜力。该系统阻断剂的作用超越了调控脑血液循环,具有更大的保护神经的作用。这为脑缺血性损伤的治疗带来了希望,为更深入地了解RAS及发现新的治疗药物找到了新的切入点。本文对目前脑RAS在脑缺血性损伤中的作用机制作一综述。     

ACE2-Ang-（1—7）-Mas轴：心血管疾病治疗的新靶点

肾素一血管紧张素系统(RAS)在哺乳动物心血管活动的调节中发挥了重要的作用.随着血管紧张素转化酶(ACE)2和血管紧张素1-7[Ang-(1-7)]特异性受体Mas的发现,形成了RAS中一个对心血管有益的新分支:ACE2-Ang-(1-7)-Mas轴.其中ACE2可以水解血管紧张素Ⅰ(Ang Ⅰ)、血管紧张素Ⅱ(AngⅡ)生成Ang-(1-7).Ang-(1-7)则通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖.这一新分支的发现为心血管疾病的治疗提供了新靶点.     

The renin–angiotensin system and prevention of age-related functional decline: where are we now?

Declining physical function is a major health problem for older adults as it is associated with multiple comorbidities and mortality. Exercise has been shown to improve physical function, though response to exercise is variable. Conversely, drugs targeting the renin–angiotensin system (RAS) pathway, including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), are also reported to improve physical function. In the past decade, significant strides have been made to understand the complexity and specificity of the RAS system as it pertains to physical function in older adults. Prior findings have also determined that interactions between antihypertensive medications and exercise may influence physical function above and beyond either factor alone. We review the latest research on RAS, exercise, and physical function for older adults. We also outline future research aims in this area, including genetic influences and clinical phenotyping, for the purpose of maintaining or improving physical function through tailored treatments.     

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

Many advances have been made in the cardiovascular field in the last several decades. Among them is the progress completed to date on the heptapeptide member of the renin–angiotensin system (RAS), angiotensin‐(1‐7) [Ang‐(1‐7)]. The peptide's beneficial actions against pathophysiological processes, such as cardiac arrhythmia, heart failure, hypertension, renal disease, preeclampsia, and even cancer are continuously being uncovered. This review encompasses the pharmacology of Ang‐(1‐7) and expounds upon the peptide's potential as a therapeutic agent against pathological processes both within and outside the cardiovascular continuum.     

Functional interactions between 7TM receptors in the Renin-Angiotensin System-Dimerization or crosstalk?

The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt- and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure. The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7 transmembrane (7TM) receptors (or G-protein-coupled receptors) such as the angiotensin II Receptors type I and II (AT1R and AT2R) and the MAS-oncogene receptor. Several findings indicate that the 7TM receptors can form both homo- and heterodimers, or higher orders of oligomers. Furthermore, dimerization may be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very difficult to establish if our observations reflect actual well-defined dimerization or merely reflect close proximity between the receptors and/or various types of functional interaction. In this review, we will present and critically discuss the current data on 7TM receptor dimerization with a clear focus on the RAS, and delineate future challenges within the field.     

Progression of hypertension and kidney disease in aging fawn-hooded rats is mediated by enhanced influence of renin–angiotensin system and suppression of nitric oxide system and epoxyeicosanoids

The fawn-hooded hypertensive (FHH) rat serves as a genetic model of spontaneous hypertension associated with glomerular hyperfiltration and proteinuria. However, the knowledge of the natural course of hypertension and kidney disease in FHH rats remains fragmentary and the underlying pathophysiological mechanisms are unclear. In this study, over the animals’ lifetime, we followed the survival rate, blood pressure (telemetry), indices of kidney damage, the activity of renin–angiotensin (RAS) and nitric oxide (NO) systems, and CYP450-epoxygenase products (EETs). Compared to normotensive controls, no elevation of plasma and renal RAS was observed in prehypertensive and hypertensive FHH rats; however, RAS inhibition significantly reduced systolic blood pressure (137 ± 9 to 116 ± 8, and 159 ± 8 to 126 ± 4 mmHg, respectively) and proteinuria (62 ± 2 to 37 ± 3, and 132 ± 8 to 87 ± 5 mg/day, respectively). Moreover, pharmacological RAS inhibition reduced angiotensin (ANG) II and increased ANG 1–7 in the kidney and thereby may have delayed the progression of kidney disease. Furthermore, renal NO and EETs declined in the aging FHH rats but not in the control strain. The present results, especially the demonstration of exaggerated vascular responsiveness to ANG II, indicate that RAS may contribute to the development of hypertension and kidney disease in FHH rats. The activity of factors opposing the development of hypertension and protecting the kidney declined with age in this model. Therefore, therapeutic enhancement of this activity besides RAS inhibition could be attempted in the therapy of human hypertension associated with kidney disease.     

Regression of cardiovascular remodeling in hypertension: Novel relevant mechanisms

Asymptomatic organ damage due to progressive kidney damage, cardiac hypertrophy and remodeling put hypertensive patients at high risk for developing heart and renal failure, myocardial infarction and stroke. Current antihypertensive treatment normalizes high blood pressure, partially reverses organ damage, and reduces the incidence of heart and renal failure. Activation of the renin-angiotensin system (RAS) is a primary mechanism of progressive organ damage and, specifically, a major cause of both renal and cardiovascular fibrosis. Currently, inhibition of the RAS system [mainly with angiotensin I converting enzyme inhibitors or angiotensin II (Ang II) receptor antagonists] is the most effective antihypertensive strategy for normalizing blood pressure and preventing target organ damage. However, residual organ damage and consequently high risk for cardiovascular events and renal failure still persist. Accordingly, in hypertension, it is relevant to develop new therapeutic perspectives, beyond reducing blood pressure to further prevent/reduce target organ damage by acting on pathways that trigger and maintain cardiovascular and renal remodeling. We review here relevant novel mechanisms of target organ damage in hypertension, their role and evidence in prevention/regression of cardiovascular remodeling and their possible clinical impact as well. Specifically, we focus on the signaling pathway RhoA/Rho kinase, on the impact of the vasodilatory peptides from the RAS and some insights on the role of estrogens and myocardial chymase in cardiovascular hypertensive remodeling.     

动脉粥样硬化大鼠B族Ⅰ型清道夫受体与肾素-血管紧张素系统的表达变化

目的 研究动脉粥样硬化大鼠主动脉B族Ⅰ型清道夫受体、血管紧张素Ⅱ1型受体和2型受体表达、血管紧张素Ⅱ水平的变化及其相互作用,探讨动脉粥样硬化的发生机制.方法 将18只大鼠随机分为对照组和动脉粥样硬化组,通过高脂喂养12周、主动脉内皮损伤和维生素D3肌肉注射建立大鼠主动脉粥样硬化模型.HE染色和Masson染色观察主动脉管壁结构和粥样硬化斑块的形成情况,放射免疫法检测血管紧张素Ⅱ的水平,免疫组织化学、Western Blot检测B族Ⅰ型清道夫受体、血管紧张素Ⅱ1型受体和2型受体的蛋白表达,实时定量逆转录聚合酶链反应检测B族Ⅰ型清道夫受体、血管紧张素Ⅱ1型受体和2型受体的mRNA表达,B族Ⅰ型清道夫受体与血管紧张素Ⅱ、血管紧张素Ⅱ1型受体和2型受体的相关性分析用直线相关分析法.结果 HE染色和Masson染色结果发现动脉粥样硬化组大鼠主动脉内粥样硬化斑块形成.动脉粥样硬化组大鼠主动脉血管紧张素Ⅱ水平较对照组明显升高(210.80±31.56 ng/L比121.26±25.32 ng/L,P<0.01).与对照组比较,动脉粥样硬化组主动脉B族Ⅰ型清道夫受体(0.83±0.19比0.16±0.03)、血管紧张素Ⅱ1型受体(1.02±0.12比0.48±0.11)和2型受体(0.97±0.24比0.13±0.03)的蛋白表达明显升高(均P<0.01),且均主要存在于胞膜和胞浆中.动脉粥样硬化组主动脉B族Ⅰ型清道夫受体(0.76±0.17比0.16±0.04)、血管紧张素Ⅱ1型受体(0.83±0.20比0.33±0.08)和2型受体(0.78±0.13比0.12±0.03)的mRNA表达较对照组明显升高(均P<0.01).动脉粥样硬化组的B族Ⅰ型清道夫受体蛋白表达与血管紧张素Ⅱ水平及血管紧张素Ⅱ1型受体表达呈显著正相关(r=0.717和r=0.711).结论 动脉粥样硬化大鼠主动脉B族Ⅰ型清道夫受体、血管紧张素Ⅱ1型受体和2型受体表达升高,且B族Ⅰ型清道夫受体表达的增高与血管紧张素Ⅱ产生增加和血管紧张素Ⅱ1型受体激活有关.     

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.     

缺血性卒中后小胶质细胞介导的炎性信号通路

小胶质细胞是中枢神经系统最主要的免疫细胞,在介导中枢神经系统免疫应答中起着关键作用.在缺血性卒中后的病理学过程中,无菌性炎症是关键因素.通过损伤相关配体与相应受体结合,小胶质细胞激活并诱导一系列炎性信号.文章从Toll样受体、炎性小体、细胞因子受体、Notch信号以及其他信号通路介绍缺血性卒中后小胶质细胞的激活和炎性反应.