MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

ACE2-Ang(1-7)-MasR轴对心血管系统保护作用的研究进展

肾素-血管紧张素系统(RAS)是人体重要的体液调节系统之一,在维持机体血压稳定和水电解质平衡中发挥了重要作用。近年来,发现了RAS系统的新支路,ACE2和Ang(1-7)等是心血管系统的关键保护因子,ACE2-Ang(1-7)-MasR轴成为了心血管疾病领域的研究热点。非经典的RAS系统ACE2-Ang(1-7)-MasR轴能够拮抗经典的ACE-AngⅡ-AT1R轴,二者共同维系机体的平衡,该轴在高血压、冠心病、心律失常和心力衰竭等心血管疾病治疗中可能成为新的治疗靶点。

妊娠高血压患者血管紧张素Ⅱ及AT1R、AT2R的表达及意义

目的:探讨妊娠高血压(HDCP)患者血管紧张素Ⅱ(AngⅡ)及AngⅡ受体-1(AT1R)和AngⅡ受体-2(AT2R)的表达及意义。方法:选取2021年1月—2022月年9月孝感市中心医院收治的90例HDCP患者作为观察组,并将观察组根据病情程度分为HDCP组、轻度子痫前期组和重度子痫前期组3个亚组,将同期产检的90例健康孕妇作为对照组。检测并比较观察组与对照组、观察组不同亚组AngⅡ水平、AT1R和AT2R阳性表达情况。结果:观察组产前母血、产后脐血AngⅡ水平低于对照组,产后母血AngⅡ水平、AT1R、AT2R总阳性率高于对照组,差异有统计学意义(P<0.05)。不同病情程度HDCP患者产前母血、产后脐血AngⅡ水平比较,HDCP组>轻度子痫前期组>重度子痫前期组;不同病情程度HDCP患者产后母血AngⅡ水平比较,HDCP组<轻度子痫前期组<重度子痫前期组;不同病情程度HDCP患者AT1R、AT2R阳性情况比较,HDCP组<轻度子痫前期组<重度子痫前期组,差异有统计学意义(P<0.05)。结论:HDCP患者母血、脐血AngⅡ存在异常表达,其AT1R、AT2R阳性率随病情加重而升高,检测上述指标有助于为HDCP发病机制、早期诊断与治疗提供参考。

AT1 receptor downregulation:A mechanism for improving glucose homeostasis

There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.

Effect of angiotensin Ⅱ type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

AIM： To investigate the effect of angiotensin II type 1 receptor blocker （ARB） and angiotensin converting enzyme inhibitor （ACEI） on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS： Forty Sprague-Dawley rats were divided into 4 groups： control, diabetes mellitus （DM）, candesartan- treated DM, and enalapril-treated DM （each group, n---10）. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/（kg · d）] and enalapril [ACEI, 10 mg/（kg · d）] were administered to rats orally for 4Wko Vascular endothelial growth factor （VEGF） and angiotensin II （Ang II） concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor （ATIR） levels were assessed at week 4 by Western blotting. RESULTS： Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control （P=0.04 and 0.005, respectively）. Vitreous ATIR increased significantly in DM compared to the other three groups （P〈0.007）. Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control （P〈0.001 and P=0.005, respectively）. No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION： Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

Effect of nuclear factor-κB and angiotensin Ⅱ receptor type 1 on the pathogenesis of rat non-alcoholic fatty liver disease

AIM: To investigate the roles of nuclear factor(NF)-κB and angiotensin Ⅱ receptor type 1(AT1R) in the pathogenesis of non-alcoholic fatty liver disease(NAFLD).METHODS: Forty-two healthy adult male SpragueDawley rats were randomly divided into three groups:the control group(normal diet), the model group,and the intervention group(10 wk of a high-fat diet feeding, followed by an intraperitoneal injection of PDTC); 6 rats in each group were sacrificed at 6, 10,and 14 wk. After sacrifice, liver tissue was taken,paraffin sections of liver tissue specimens were prepared, hematoxylin and eosin(HE) staining was performed, and pathological changes in liver tissue(i.e., liver fibrosis) were observed by light microscopy.NF-κB expression in liver tissue was detected by immunohistochemistry, and the expression of AT1 R in the liver tissue was detected by reverse transcriptionpolymerase chain reaction(RT-PCR). The data are expressed as mean ± SD. A two-sample t test was used to compare the control group and the model group at different time points, paired t tests were used to compare the differences between the intervention group and the model group, and analysis of variance was used to compare the model group with the control group. Homogeneity of variance was analyzed with single factor analysis of variance. H variance analysis was used to compare the variance. P < 0.05 wasconsidered statistically significant.RESULTS: The NAFLD model was successful after 6wk and 10 wk. Liver fibrosis was found in four rats in the model group, but in only one rat in the intervention group at 14 wk. Liver steatosis, inflammation, and fibrosis were gradually increased throughout the model. In the intervention group, the body mass,rat liver index, serum lipid, and transaminase levels were not increased compared to the model group.In the model group, the degree of liver steatosis was increased at 6, 10, and 14 wk, and was significantly higher than in the control group(P < 0.01). In the model group, different degrees of liver cell necrosis were visible and small leaves, punctated inflammation,focal necrosis, and obvious ballooning degeneration were observed. Partial necrosis and confluent necrosis were observed. In the model group, liver inflammatory activity scores at 6, 10, and 14 wk were higher than in the control group(P < 0.01). Active inflammation in liver tissue in the intervention group was lower than in the model group(P < 0.05). HE staining showed liver fibrosis only at 14 wk in 4/6 rats in the model group and in 1/6 rats in the intervention group. NF-κB positive cells were stained yellow or ensemble yellow,and NF-κB was localized in the cytoplasm and/or nucleus. The model group showed NF-κB activation at6, 10, and 14 wk in liver cells; at the same time points,there were statistically significant differences in the control group(P < 0.01). Over time, NF-κB expression increased; this was statistically lower(P < 0.05) at14 weeks in the intervention group compared to the model group, but significantly increased(P < 0.05)compared with the control group; RT-PCR showed that AT1 R mRNA expression increased gradually in the model group; at 14 wk, the expression was significantly different compared with expression at 10 weeks as well as at 6 weeks(P < 0.05). In the model group, AT1 R mRNA expression was significantly higher than at the same time point in the control group(P <0.01).CONCLUSION: With increasing severity of NAFLD,NF-κB activity is enhanced, and the inhibition of NF-κB activity may reduce AT1 R mRNA expression in NAFLD.

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

Evaluation of a novel angiotensin II receptor 1 antagonist intesartan as anti-hypertension drug

Aim The preclinical studies of a novel angiotensin II receptor 1 antagonist 2-（4-（ （1,7＇-dimethyl-2＇- propyl-1H ,3 ＇H-2,5＇-bibenzo [ d ] imidazol-3＇-yl ） methyl） -1H-indol-l-yl ） benzoic acid （ intesartan ）. Methods The affinity to AT1 receptor of intesartan was tested through radioactive receptor binding assay by -y-counter. The anti-hypertensive activity in spontaneously hypertensive rats （SHRs） at different doses in vivo was tested by tail noninvasive arterial blood pressure measurement system. Pharmacokinetic parameters were analyzed by high per- formance liquid chromatography （HPLC） method. Besides, acute toxicity tests in ICR and Ames reverse mutation assay in tester strain （TA97, TA98, TA100 and TA102） was also detected. Results The binding assays sugges- ted that intesartan displayed high affinity to angiotensin II AT1 receptor with an ICs0 value of （0.36 ± 0. 18） nmol · L^-1. In vivo anti-hypertensive experiments showed that intesartan had an efficient and long-acting effect in reduc- ing blood pressure which could last more than 24 h at the doses of 2 mg· kg^-1, 5 mg · kg^-1 , and 10 mg · kg^-1 in spontaneously hypertensive rats. The minimum effective dose of it was 2 mg · kg^-1 and the T/P value was 54. 18%. Acute toxicity tests suggested that intesartan was safe with the LDs0 value of 526.20 mg · kg^-1. Ames assay proved that it would not cause the mutations of salmonella typhimurium. And the pharmacokinetic experiments showed that it could be absorbed efficiently and metabolized smoothly both in blood and in tissues in wistar rats. Conclusions Intesartan could be considered as a novel anti-hypertension candidate with efficient, long-acting and low toxicity chracteristics.

Pinocembrin inhibits angiotensinⅡ-induced vasoconstriction in a Ca^(2+)-dependent and Ca^(2+)-independent manner through blocking AT_1R in the rat aorta

OBJECTIVE To investigate the vasorelaxant effect of pinocembrin(5,7-dihydroxyflavanone),one of the main flavonoids in propolis,on angiotensinⅡ(AngⅡ)induced vasoconstriction and the molecular mechanism of action.METHODS The isometric vascular tone was measured in thoracic aortic rings from SD rat,and the effects of pinocembrin on the single dose and concentration cumulative response curves of AngⅡ were recorded.The binding of pinocembrin to the angiotensin type 1 receptor(AT1R)was studied by using molecule docking analysis.Intracellular[Ca2+]([Ca2+]i)was measured with Fura2/AM in VSMCs.The phosphorylation levels of myosin light chain 2(MLC2)and myosin phosphatase target unit 1(MYPT1),and protein level of Rho kinase 1(ROCK1)in the rat aortic rings were detected by Western blotting.RESULTS Pinocembrin was observed to inhibit AngⅡ-induced vasoconstriction in rat aortic rings with either intact or denuded endothelium.In endothelium-denuded tissues,pinocembrin(pD′2 4.28±0.15)counteracted the contractions evoked by cumulative concentrations of AngⅡ.In a docking model,pinocembrin showed effective binding at the active site of AT1R.Pinocembrin was shown to inhibit both AngⅡ-induced Ca2+ release from internal stores and Ca2+ influx.Moreover,the increase in the phosphorylation of MLC2 and MYPT1,and the increased protein level of ROCK1 induced by AngⅡ was blocked by pinocembrin.CONCLUSION Pinocembrin inhibits AngⅡ-induced rat aortic ring contraction in a Ca2+-dependent and Ca2+-independent manner via blocking AT1R.

苓桂术甘汤对心肌梗死后心室重构模型大鼠AngⅡ、Ald和AT_1R的影响

目的:观察苓桂术甘汤对心室重构模型大鼠AngⅡ、Ald及AT1R的影响,探讨其干预心室重构的机制。方法:冠脉结扎法复制大鼠模型2周后,各组连续给药4周,采用ELISA法检测血清AngⅡ、Ald含量,采用Western blot法检测心肌组织AT1R表达。结果:模型组与假手术组比较AngⅡ、Ald含量显著升高,AT1R表达显著增加(P<0.01);苓桂术甘汤各剂量组与模型组比较AngⅡ、Ald含量显著降低,AT1R表达显著抑制(P<0.01)。结论:苓桂术甘汤干预心室重构的机制与调控RAAS相关因子有关。

AT_1R-CaN信号通路在乳鼠肥大心室肌细胞Nav1.5蛋白表达调控中的作用

目的:探讨血管紧张素Ⅱ1型受体(AT_1R)调神经磷酸酶(CaN)信号通路在乳鼠肥大心室肌细胞Nav1.5 mRNA和蛋白表达调控中的作用。方法:分离1日龄SD乳大鼠心室获心室肌细胞,分为对照(control)组、苯肾上腺素(PE)组、氯沙坦(Los)+PE组和环孢素A(CsA)+PE组;重组腺病毒shRNA干扰载体介导CaN A亚基β亚型(CnAβ)基因沉默分为腺病毒空载体(Ad-Null)组、Ad-Null+PE组、重组腺病毒CnAβshRNA1(AdCnAβshRNA1)组和Ad-CnAβshRNA1+PE组。实时荧光定量逆转录PCR检测脑钠尿肽(BNP)、β-肌球蛋白重链(β-MHC)和Nav1.5的mRNA表达。Western blot法检测全细胞提取蛋白CnAβ和Nav1.5的表达。结果:PE干预24 h明显增加心室肌细胞蛋白/DNA比值、细胞BNP和β-MHC的mRNA表达以及细胞面积;上调CnAβ蛋白表达,下调Nav1.5蛋白表达。CsA和Los干预明显抑制PE干预的上述效应。PE下调Nav1.5的mRNA表达,但Los和CsA不能抑制此种效应。Ad-CnAβshRNA1沉默乳鼠心室肌细胞CnAβ基因抑制了PE对BNP mRNA的上调作用,抑制了PE对Nav1.5蛋白表达的下调作用。结论:AT_1R-CaN信号通路参与调控培养的乳鼠肥大心室肌细胞Nav1.5蛋白表达的调控。

AT_1R基因及CYP基因多态性与妊娠期高血压疾病的相关性

目的探讨妊娠期高血压疾病的分子遗传学机制。方法采用聚合酶链反应—限制性内切酶片段长度多态性技术(PCR-RFLP)分别检测87例妊娠期高血压疾病患者(观察组)和175例正常人(对照组)血管紧张素Ⅱ-1型受体(AT1R)基因A1166-C和醛固酮合成酶(CYP11B2)基因-344 T/C突变位点基因型。基因型及等位基因患妊娠期高血压疾病的风险率以比数比(OR)与95%可信区间(95%CI)表示。结果观察组中AT1R基因的AC基因型频率为33.3%,C等位基因频率为17.2%,相对于AA基因型、A等位基因,OR值分别为1.803、1.711;CYP11B2基因的TC和CC基因型频率分别为40.2%和17.2%,C等位基因频率为37.4%,相对于TT基因型、T等位基因,OR值分别为1.577、6.081、2.114;AT1R和CYP11B2联合基因型分析显示,相对于AA-TT联合基因型,同时携带AC-TC、AA-CC、AC-CC联合基因型的OR值分别为2.407、6.296、7.870。结论AT1R基因1166C和CYP11B2基因-344C点突变的等位基因可能增加妊娠期高血压疾病的遗传易感性;二者可能共同参与妊娠期高血压疾病的发生。

AT_1R基因和ACE基因多态性与高血压病的相关性分析

目的：本研究旨在探讨中国人血管紧张素Ⅱ１ 型受体（ＡＴ１Ｒ）基因和血管紧张素转化酶（ＡＣＥ）基因与高血压病（ＥＨ）的相关情况，以及两种基因在发病中的相互关系。方法：以１３７ 例ＥＨ患者（其中Ⅱ，Ⅲ期８９ 例）和６３ 例健康人为对象，用ＰＣＲ／ＤｄｅＩ酶解检测位于ＡＴ１Ｒ基因３＇－ＵＴＲ的Ａ１１６６Ｃ突变，并用ＰＣＲ检测ＡＣＥ基因内含子１６ 的插入／缺失（Ｉ／Ｄ）多态性标记。结果：（１）ＥＨ 组的ＡＴ１Ｒ基因的ＡＣ基因型和Ｃ等位基因频率明显高于对照组（ＡＣ基因型０．２３ ｖｓ０．０９，Ｐ＜ ０．０５；Ｃ等位基因０．１３ ｖｓ０．０５，Ｐ＜ ０．０５），尤其ＥＨ（Ⅱ，Ⅲ）组显著高于对照组（Ｐ＜ ０．０１）；（２）ＥＨ组的ＡＣＥ基因的ＤＤ基因型及Ｄ等位基因频率与对照组比较无明显差别Ｐ＞ ０．０５），但ＥＨ（Ⅱ，Ⅲ）组的ＤＤ基因型及Ｄ等位基因频率却显著高于对照组（Ｐ＜ ０．０１）；（３）ＡＴ１Ｒ基因和ＡＣＥ基因的多态性对ＥＨ的影响作用可能独立于年龄、ＢＭＩ、血压、血脂以及血浆ＰＲＡ和ＡｎｇⅡ水平；（４）ＥＨ 及ＥＨ（Ⅱ，Ⅲ）患者的ＡＴ１Ｒ 基因型和ＡＣＥ型基因组成联合基因型的频率分布与对照组比较无统计学差异（Ｐ＞ ０．０５）；提示?

Multiple templates-based homology modeling and docking analysis of angiotensin Ⅱ type 1 receptor

Using the latest reported homologous Chemokine receptors (PDB ID:3ODU,3OE0 and 3OE6) as templates,twenty models of angiotensin II (Ang II) type 1 (AT1) receptor (known as p30556) were generated by multiple templates homology modeling.According to the results of the initial validation of these twenty models,the model 0020 was finally chosen as the best one for further studies.Then,a 2 ns molecular dynamic (MD) simulation for model 0020 was conducted in normal saline (0.9%,w/V) under periodical boundary conditions,which was followed by docking studies of model 0020 with several existing AT1 receptor blockers (ARBs).The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects.The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results,such as hydrogen bonds,hydrophobic interactions,and especially cation-π interactions and π-π interactions which have never been reported before.This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design.

Antagonism of Angiotensin II AT1 Receptor and Silencing of CD44 Gene Expression Inhibit Cardiac Fibroblast Activation via Modulating TGF-<i>β</i>1/Smad Signaling Pathway

Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not well understood. This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts were isolated from the neonatal rat hearts;the activation of fibroblasts was evaluated using the assays of cell viability and migration, and silencing of CD44 gene expression was conducted with small interfering RNA (siRNA). Results showed that Ang II significantly increases the cell proliferation and migration in a dose-dependent manner. Upon activation, the protein levels of TGF-β1, Smad2, Smad4 and collagen I were significantly increased (all p < 0.05 vs. unstimulated cells), but these changes were significantly downregulated by the AT1 receptor blocker, telmisartan (all p < 0.05 vs. Ang II activated cells). Furthermore, mRNA and protein level of CD44 were upregulated, and there was a linear correlation between CD44 and TGF-β1 as demonstrated by Pearson correlation analysis (r = 0.955, p < 0.01). Gene transfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of CD44 mRNA and protein, significantly reduced the production of collagen I. In summary, these results indicate that the proliferation, migration and collagen production from Ang II activated cardiac fibroblasts are potentially mediated by the AT1 receptor and CD44. Such a signaling mechanism could be crucial for the production of collagen and the development of tissue fibrosis in the heart.

老年原发性高血压患者AT_1-R基因A1166C多态性及降压药物对其的影响

目的 观察老年原发性高血压患者血管紧张素Ⅱ 1型受体 (AT1-R)基因A116 6C多态性的分布及不同基因型高血压患者对AT1受体拮抗剂 (AT1RB)和血管紧张素转换酶抑制剂 (ACEI)降压治疗的反应。方法 PCR RFLP法检测上海地区 186例老年高血压患者AT1 R基因 3’非编码区的A116 6C变异 ,测定 116 6C等位基因频率。选取 6 0例高血压患者按基因型分成AA和AC两组 ,随机进入AT1RB和ACEI治疗组 ,共 5 7例完成 2 4周随访 (AA =41;AC =16 ) ,比较治疗前后 2 4小时动态血压监测结果。结果 (1) 116 6C等位基因频率为 0 0 6 2 ;(2 )AT1RB组AA基因型高血压患者总体、白天、夜间的SBP和DBP均较治疗前下降 7 36 %、7 6 3%、6 81%和 6 4 8%、6 4 5 %、7 4 3%;AC基因型高血压患者总体的SBP及白天的SBP、DBP均较治疗前下降 5 2 0 %和 5 6 2 %、5 5 9%。ACEI组AA和AC基因型高血压患者总体和白天SBP的下降幅度分别为 6 18%、7 13%和 4 99%、5 75 %,经配对t检验均P <0 0 5。不同药物不同基因型患者降压幅度经 2× 2方差分析均P >0 0 5。结论 (1)国内老年高血压人群 116 6C等位基因的分布频率较低 ;(2 )AT1RB和ACEI对不同AT1 R基因型老年高血压患者均有降压效应 ,其疗效与是否携带 116 6C等位基因无关。

Activation of angiotensin Ⅱ type 1 receptors in the median preoptic nucleus induces a diuretic and natriuretic response in rats

Objective： To investigate the effect of activation of angiotensin Ⅱ（AngⅡ） type 1 （AT1） receptors in the median preoptic nucleus （MnPO） of rats on renal sodium excretion. Methods： After anesthesia, the rats were injected into the MnPO via an implanted cannula. Urine samples were collected via a bladder cannula, and the urine sodium concentration was assayed with flame spectrophotometry. The serum level of endogenous digitalis-like factor （EDLF） and Na^＋,K^＋-ATPase activity in the renal cortex tissue were assayed respectively with a radioimmunoassay and with an ammonium molybdophosphate-based kit. Results： Both the urinary volume and the sodium excretion peaked 60 min after AngⅡ was administered into the MnPO. The responses were accompanied by an increase in serum EDLF and a decrease in Na^＋,K^＋-ATPase activity in the renal cortex. The responses of diuresis and natriuresis, as well as an increase in serum EDLF and a decrease in Na^＋,K^＋-ATPase activity in the renal cortex induced by MnPO adminstration with AngⅡ were inhibited by pior treatment with the AngⅡ receptor blocking agent losartan into the MnPO. Conclusion： These results suggest that activation of AT1 receptors in the MnPO of rat induces diuretic and natriuretic responses. The responses are associated with an increase release of EDLF and with the inhibition of Na^＋,K^＋-ATPase activity in renal cortex tissue.

不同年龄自发性高血压大鼠肾脏AT_1R和AT_2R的表达

目的本研究观察不同月龄自发性高血压大鼠(SHR)肾脏AT1R和AT2R表达,初步探讨AT1R和AT2R在高血压发生、发展过程中的可能作用。方法1月龄组(S1)、2月龄组(S2)、3月龄组(S3)、6月龄组(S6)和9月龄组(S9)雄性SHR共5组,每组各6只,各组均有相应月龄匹配的Wistar-Kyoto大鼠(WKY)作对照。采用RBP-I型大鼠血压心率测定仪测量大鼠尾动脉收缩压(SBP);放免法测定血浆血管紧张素Ⅱ(AngⅡ);免疫组化染色结合计算机图像分析方法测定肾脏AT1R和AT2R表达水平。结果(1)SHR SBP随着月龄的增加而上升,S6后趋于稳定。(2)1个月后SHR血浆AngⅡ浓度均高于S1(P<0.05),而S2、S3、S6和S9之间无明显差别(P>0.05);1个月后SHR血浆AngⅡ浓度均高于相应配对的WKY组(P<0.05);而WKY各月龄组均无明显差别(P>0.05)。(3)SHR肾脏AT1R随着月份的增加而增加(P<0.05),且高于相应配对的WKY组(P<0.05)。SHR肾脏AT2R随着月份的增加而降低,S6明显降低(P<0.05),S6和S9比较无明显差别(P>0.05);且均低于相应配对的WKY组(P<0.05)。WKY各月龄组AT1R和AT2R无明显差别(P>0.05)。结论SHR肾脏AT1R表达水平比WKY高,并随着年龄的增加而递增;AT2R表达水平比WKY低,并随着年龄的增加而降低。

哮喘小鼠肺脏组织肾素-血管紧张素系统相关组分表达及AT_1R拮抗剂对其影响

目的:探讨肾素-血管紧张素系统(RAS)与哮喘发生的关系,为哮喘发病机制的研究和治疗提供理论依据。方法:复制小鼠哮喘模型,小鼠分为对照组、模型组、坎地沙坦低剂量组及高剂量组,采集小鼠血清,测量血清中血管紧张素Ⅱ(AngⅡ)与血管紧张素Ⅰ(AngⅠ)的含量;通过Western blotting和RT-PCR观察RAS中血管紧张素原(AGT)、血管紧张素转换酶(ACE)、血管紧张素Ⅱ1型受体(AT1R)和2型受体(AT2R)在各组小鼠肺组织中的表达。结果:模型组小鼠血清AngⅡ含量较对照组增高(P<0.05),坎地沙坦组与模型组比较无明显变化(P>0.05)。各组小鼠血清中AngⅠ含量比较差异无统计学意义(P>0.05)。模型组小鼠AT1R和ACE蛋白表达较对照组明显增加(P<0.05),坎地沙坦组AT1R表达与模型组比较明显降低(P<0.05),ACE无明显变化(P>0.05)。AT2R蛋白表达各组间比较差异无统计学意义(P>0.05)。模型组小鼠ACE mRNA表达较对照组明显增加(P<0.05),坎地沙坦组与模型组比较差异无统计学意义(P>0.05)。模型组小鼠AT1R mRNA表达较对照组明显增加(P<0.05),坎地沙坦组较模型组明显降低(P<0.05)。模型组AT2R mRNA较对照组明显降低(P<0.05),坎地沙坦组较模型组明显增加(P<0.05)。各组AGT mRNA表达无明显变化(P>0.05)。结论:在小鼠哮喘发病过程中,RAS活化参与了哮喘的发病过程,并且AT1R拮抗剂坎地沙坦可以逆转ACE、AT1R和AT2R表达的改变。