肾素- 血管紧张素- 醛固酮系统与原发性高血压病的关系

目的:探讨血浆肾素-血管紧张素系统与原发性高血压病的关系。方法:采用病例-对照研究设计,入选125例原发性高血压病患者与60例血压正常健康体检者为对照组。采用放射免疫方法测定立位、卧位血浆肾素活性(PRA),醛固酮(ALD)浓度及血管紧张素Ⅱ(AngⅡ)浓度。结果:原发性高血压患者,立位、卧位血浆PRA均低于正常对照组(P<0.05),而ALD浓度及AngⅡ浓度均高于正常对照组(P<0.05)。根据高血压病1级、2级、3级分组,立位、卧位血浆PRA均依次降低(P<0.05);而ALD浓度及AngⅡ浓度依次升高(P<0.05)。结论:肾素-血管紧张素-醛固酮系统与原发性高血压病的发病关系密切,血浆PRA水平、AngⅡ及ALD浓度有望成为原发性高血压病分级的有效指标;降低原发性高血压患者AngⅡ及ALD量是治疗高血压病的关键,血浆AngII、ALD也有望成为评价原发性高血压病疗效的指标。     

血管紧张素转换酶2-血管紧张素1-7-Mas轴对血管作用的研究进展

血管紧张素转换酶2（ACE2）和Mas受体的发现使人们对肾素-血管紧张素（RAS）有了更全面的认识。ACE2可水解血管紧张素Ⅰ和血管紧张素Ⅱ直接或间接生成血管紧张素1-7（Ang 1-7）,并与高血压的形成密切相关。Ang 1-7主要通过Mas受体引起血管舒张、抑制细胞增殖。ACE2-Ang1-7-Mas轴的发现为RAS的研究、高血压等心血管疾病的防治和新药开发提供了新的思路和方向。     

血管紧张素Ⅱ2型受体基因缺失不影响肾素-血管紧张素系统

基于目前对血管紧张素Ⅱ2型受体(AT2)功能的认识,认为血管紧张素Ⅱ1型受体(AT1)和AT2受体有相互拮抗作用.依据上述论点,本研究利用AT2受体基因敲出小鼠,观察了AT2受体缺失后是否造成肾素-血管紧张素系统其它成分代偿性紊乱.结果发现,AT2受体基因缺失小鼠血浆和肾组织中血管紧张素Ⅱ的浓度以及肾组织中肾素、AT1A受体的基因表达均未发生明显改变,表明AT2受体缺失未对肾素-血管紧张素系统产生显著影响,AT2受体的功能已被代偿,但代偿途径尚有待于进一步研究.     

肾素-血管紧张素系统的新调节分子:ACE2

血管紧张素转化酶（angiotensin—converting enzyme,ACE）为含锌的金属蛋白酶,是肾素-血管紧张素系统（renin—angiotensin system,RAS）重要的调节分子。血管紧张素转化酶2（angiotensin—con—verting enzyme2,ACE2）是迄今发现的唯一的ACE同系物（homologue）,它主要分布于睾丸、肾脏和心脏。ACE2可水解血管紧张素Ⅰ（angiotensinⅠ,AngⅠ）和血管紧张素Ⅱ（angiotensinⅡ,AngⅡ）羧基端的1个氨基酸残基,分别形成Ang1-9和有血管舒张作用的Ang1-7。ACE2的生理病理作用还不甚明了,传统的ACE抑制剂不能抑制ACE2的活性。ACE2在心血管、肾脏系统的作用可能与ACE相反．与ACE共同调节心脏、肾脏等脏器的正常功能。     

急性高原病患者血浆肾素—血管紧张素—醛固酮系统及脑脊液变化

急性高原病通常分为急性高原反应(HAAR)、高原肺水肿(HAPE)和高原昏迷(HACC)三型。对其发病机理目前还存在着争议,为进一步探讨其发病机理,采用自身对比实验,观察了HAAR、HAPE各20名患者发病时及治愈后的血浆肾素(PRA)-血管紧张素(AⅡ)-醛固酮(ALD)系统及脑脊液变化。     

利钠肽系统与肾素-血管紧张素-醛固酮系统在心力衰竭中交互作用

慢性心力衰竭是以高发病率、高入院率及高死亡率为特征的临床综合征,也是各种心血管疾病发展的终末阶段。神经激素系统的激活在心力衰竭病理生理中起着关键作用,其以肾素-血管紧张素-醛固酮系统(RAAS)、交感神经系统(SNS)及利钠肽系统(NPs)为主要组成部分。在心衰的病理生理中,NPs与RAAS存在交互作用,其对于与心功能不全相关的血液动力学改变与组织重塑起重要的作用,并且最终可导致心衰的恶化。因此,能够同时作用于RAAS与NPs,并且能够纠正两者间调节紊乱的干预措施,对于慢性心衰的治疗将具有良好的疗效。本文将主要对RAAS、NPs及NPs与RAAS的交互作用在心衰中的病理生理作用进行综述,并展望针对NPs与RAAS的交互作用的临床应用前景。     

肾素—血管紧张素系统——应激激素反应系统

各种急性与慢性庆激时,循环血中及脑、心血管、肾上腺等组织中血管紧张素Ⅱ（ＡⅡ）显著增多;人剧烈运动后血浆ＡⅡ与皮质醇一样均剧烈增加,在慢性应激性高血压动物循环及组织中,ＡⅡ含量持续地增高。还发现高浓度ＡⅡ对肾上腺糖皮质激素的分泌有直接的刺激作用,而组织ＡⅡ含量增多又受肾上腺素能β受体的激发。根据近年来的系列工作,并结合文献,我们认为ＡⅡ是一种重要的应激激素;肾素－血管紧张素系统是一个应激激素反应系     

血管紧张素II2型受体基因缺失不影响肾素—血管紧张素系统

基于目前对血管紧张素Ⅱ２型受体（ＡＴ２）功能的认识,认为血管紧张素Ⅱ１型受体（ＡＴ１）和ＡＴ２受体有相互拮抗作用。依据上述论点,本研究利用ＡＴ２受体基因敲出小鼠,观察了ＡＴ２受体缺失后是否造成肾素－血管紧张素系统其它成分代偿性紊乱。结果发现,ＡＴ２受体基因缺失小鼠血浆和肾组织中血管紧张素Ⅱ的浓度以及肾组织中肾素、ＡＴ１Ａ受体的基因表达均未发生明显改变,表明ＡＴ２受体缺失未对肾素－血管紧张素系统产生     

作为肾素-血管紧张素系统调节器和SARS病毒受体的人血管紧张素转换酶2

人血管紧张素转换酶2(ACE2)是目前已知的惟一的人血管紧张素转换酶(ACE)的同源物,是一种新型的金属羧肽酶,很多特性与ACE截然不同.ACE2在肾素-血管紧张素系统(RAS)中具有独特的作用,调节心脏功能和机体血压.最近ACE2被鉴定为SARS病毒的功能受体.ACE2已经成为目前药物研发的新靶点.对ACE2的认识才刚刚开始,有待进-步深入研究.     

血管紧张肽转化酶2与肾素-血管紧张肽系统的研究进展

肾素-血管紧张肽系统（RAS）在维持血压稳态、水盐平衡,及局部组织器官的正常功能等方面具有重要的作用。局部RAS的失衡将导致这些器官的疾病。血管紧张肽转化酶2（ACE2）是ACE的同源物,作为RAS的重要负调节因子,平衡血管紧张肽Ⅱ的产生,维持循环系统和局部组织中RAS的稳态。本文综述了在心血管、肺、肾、肝等器官的多种急、慢性疾病患者或动物模型中,RAS与ACE2所发挥的重要作用。     

Calreticulin enhances B2 bradykinin receptor maturation and heterodimerization

In different native tissues and cells the receptor for the vasodepressor bradykinin, B₂, forms dimers with the receptor for the vasopressor angiotensin II, AT₁. Because AT₁/B₂ heterodimers may contribute to enhanced angiotensin II-stimulated signaling under pathophysiological conditions, we analyzed mechanisms of AT₁/B₂ heterodimerization. We found that efficient B₂ receptor maturation was a prerequisite for heterodimerization because only the fully mature B₂ receptor was capable to interact with AT₁. To identify chaperones involved in B₂ receptor maturation and heterodimerization we performed microarray gene expression profiling of human embryonic kidney (HEK293) cells. The expression of the chaperone calreticulin was up-regulated in cells with efficient B₂ receptor maturation. Vice versa, upon down regulation of calreticulin expression by RNA interference, B₂ receptor maturation and AT₁/B₂ receptor heterodimerization were significantly impaired. Concomitantly, the B₂ receptor-mediated enhancement of AT₁-stimulated signaling was reduced. Thus, calreticulin enhances B₂ receptor maturation and heterodimerization with AT₁.     

Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice

The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21 days (10 mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action.     

Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immune-mediated nephritic kidney through counter-activation of angiotensin II type 2 receptor

The relative roles of angiotensin II (Ang II) type 1 receptor (AT(1)R) and Ang II type 2 receptor (AT(2)R) in immune-mediated nephritis are unknown, and the effect of the blockade of AT(1)R and its indirect counter-activation of AT(2)R relative to the anti-fibrotic action in this disease is unclear. To address this question, we studied the role of AT(1)R and AT(2)R in anti-glomerular basement membrane nephritis in SJL mice. Groups of mice were treated with either an AT(1)R antagonist (CGP-48933; CGP group), an AT(2)R antagonist (PD-123319; PD group), both (CGP/PD group), or a vehicle (PCt group) from Day 29 to 56. At Day 56 post-treatment, fibrosis-related parameters such as interstitial matrix deposition, and the expression of genes of TGF-beta1, plasminogen activator inhibitor-1, and type I collagen were significantly reduced in the kidney in the CGP group. There were no significant effects on these parameters in the PD group. However, this anti-fibrotic action by CGP-48933 was totally abolished by co-treatment with PD-123319 in the CGP/PD group. The gene expression of renin was significantly increased in the kidneys in the CGP and CGP/PD groups, suggesting that CGP-48933 had increased Ang II generation in those groups. In conclusion, counter-activation of AT(2)R by increased Ang II under AT(1)R blockade likely conferred an anti-fibrotic protection in this model.     

PKA-mediated effect of MAS receptor in counteracting angiotensin II-stimulated renal Na-ATPase

We showed previously that angiotensin-(1-7) [Ang-(1-7)] reversed stimulation of proximal tubule Na⁺-ATPase promoted by angiotensin II (Ang II) through a d-ala⁷-Ang-(1-7) (A779)-sensitive receptor. Here we investigated the signaling pathway coupled to this receptor. According to our data, Ang-(1-7) produces a MAS-mediated reversal of Ang II-stimulated Na⁺-ATPase by a Gs/PKA pathway because: (1) the Ang-(1-7) effect is reversed by GDPβS, an inhibitor of trimeric G protein and Gs polyclonal antibody. Cholera toxin, an activator of Gs protein, mimicked it; (2) in the presence of Ang II, Ang-(1-7) increased the PKA activity 10-fold; (3) the peptide inhibitor of PKA blocked the Ang-(1-7) effect on Ang II-stimulated Na⁺-ATPase; (4) Ang-(1-7) reverses the Ang II-stimulated PKC activity; (5) cAMP mimicked the Ang-(1-7) effect on the Ang II-stimulated Na⁺-ATPase. Our results provide new understanding about the signaling mechanisms coupled to MAS receptor-mediated renal Ang-(1-7) effects.     

Regulation of insulin sensitivity,insulin production,and pancreatic β cell survival by angiotensin-(1-7) in a rat model of streptozotocin-induced diabetes mellitus

The aim of this study is to determine the antidiabetic activity of Ang-(1-7), an important component of the renin–angiotensin system, in a rat model of streptozotocin (STZ)-induced type 2 diabetes mellitus (DM). A total of 36 male Wistar rats were randomly divided into 3 groups: control group fed standard laboratory diet, DM group fed high-fat diet and injected with STZ, and Ang-(1-7) group receiving injection of STZ followed by Ang-(1-7) treatment. Body weight, blood glucose levels, fasting serum Ang II and insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The pancreas was collected for histological examination and gene expression analysis. Notably, the Ang-(1-7) group showed a significant decrease in fasting blood glucose and serum Ang II levels and HOMA-IR values and increase in fasting serum insulin levels. Pancreatic β cells in the control and Ang-(1-7) groups were normally distributed in the center of pancreatic islets with large clear nuclei. In contrast, pancreatic β cells in the DM group had a marked shrinkage of the cytoplasm and condensation of nuclear chromatin. Ang-(1-7) treatment significantly facilitated insulin production by β cells in diabetic rats. The DM-associated elevation of inducible nitric oxide synthase (iNOS), caspase-3, caspase-9, caspase-8, and Bax and reduction of Bcl-2 was significantly reversed by Ang-(1-7) treatment. Taken together, Ang-(1-7) protects against STZ-induced DM through improvement of insulin resistance, insulin secretion, and pancreatic β cell survival, which is associated with reduction of iNOS expression and alteration of the Bcl-2 family.     

Cancer stem cell-like cells from a single cell of oral squamous carcinoma cell lines

Angiotensin II (AngII) and its type receptor (AT1-R) play important roles in the development of cardiac hypertrophy. Low level of high density lipoprotein (HDL) is also an independent risk factor for cardiac hypertrophy. We therefore investigated in the present study whether HDL inhibits cardiac hypertrophy relatively to inhibition of AngII and AT1-R in both in vitro and in vivo experiments. Stimulation of cultured cardiomyocytes of neonatal rats with AngII for 24 h and infusion of AngII in mice for 2 weeks resulted in marked cardiac hypertrophic responses including increased protein synthesis, enlarged sizes of cardiomyocytes and hearts, upregulated phosphorylation levels of protein kinases and reprogrammed expression of specific genes, all of which were significantly attenuated by the treatment with HDL. Furthermore, AngII-treatment induced upregulation of AT-R expression either in cultured cardiomyocytes or in hearts of mice and HDL significantly suppressed the upregulation of AT1-R. Our results suggest that HDL may abrogate AngII-induced cardiac hypertrophy through downregulation of AT1-R expression.