Induction of Angiotensinogen mRNA in Hepatocytes by Angiotensin II and Glucocorticoids

ABSTRACT

In isolated rat hepatocytes, exposed to angiotensin II and glucocorticoids, angiotensinogen mRNA increased within 30-60 min, and angiotensinogen secretion with a time lag of about 2 hours. After 4 hours, angiotensinogen mRNA, estimated by liquid hybridization with radiolabeled cRNA, was 5.9 ± 0.4 in control, and 10.8 ± 0.8, 11.7 ± 0.4, 16.1 ± 0.8 and 21.7 ± 0.2 pg/μg of total RNA in cells exposed to angiotensin II (9 nM and 90 nM), hydrocortisone (100 μM) and dexamethasone (10 μM) respectively. The corresponding secretion rates of angiotensinogen were 72 ± 7, 124 ± 4, 132 ± 12, 220 ± 19 and 217 ± 18 fmol angiotensinogen/mg wet weight/hour. Thus, angiotensin II stimulates angiotensinogen synthesis and secretion by acting at a pretranslational site.     

Effects of Growth Hormone and Estrogen on Rat Angiotensinogen Quantified by an Enzyme Linked Immunosorbent Assay

An enzyme linked immunosorbent assay for rat angiotensinogen was developed based on one monoclonal antibody with high affinity for angiotensinogen and des-angiotensin 1–angiotensinogen and rabbit polyclonal antibodies for angiotensinogen was developed. Serum levels of angiotensinogen were lower in female than in male rats but increased significantly after hypophysectomy. Estrogen substitution after hypophysectomy had no further stimulatory or inhibitory influence. In hypophysectomized animals continuous and intermittent growth hormone administration had clearly different effects. The results indicate that the sexually dimorphic secretion of growth hormone is involved in the regulation of circulating angiotensinogen concentrations in the rat.     

Genetic polymorphisms in the renin-angiotensin system: relevance for susceptibility to cardiovascular disease

The renin–angiotensin system plays an important role in the pathogenesis of cardiovascular disease. Cloning of the human genes coding for the angiotensin-converting enzyme, angiotensinogen, and angiotensin II type 1 receptor has led to the discovery of several polymorphisms, which may be implicated in the pathogenesis of cardiovascular disease. The deletion/insertion (D/I) polymorphism of the angiotensin-converting enzyme gene is associated with hypertension in men, left ventricular hypertrophy in untreated hypertensive patients, various atherosclerotic cardiovascular complications, and microvascular disorders. The M235T polymorphism of the angiotensinogen gene may be associated with a higher risk of hypertension. The A1166C polymorphism of the angiotensin II type 1 receptor gene is probably correlated with hypertension and through an epistatic interaction with the D/I polymorphism of the angiotensin-converting enzyme gene possibly also with coronary heart disease. Several other gene polymorphisms, in particular those in the promoter area of the angiotensinogen gene, have been studied in relation to cardiovascular disease. Based on the insights gained from the reports summarized in this review article, population-based genetic studies of nuclear families are currently being conducted in Belgium and in the People's Republic of China with blood pressure and hypertension as the main outcome variables.     

Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA-salt hypertension

In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.     

The intrarenal renin-angiotensin-system

Summary The localization of renin, converting enzyme (CE) and angiotensin II (ANG II) in the kidneys of rats and mice was investigated with immunocytochemical methods. According to the presence and specific intrarenal localization of these components of the renin-angiotensin-system (RAS) our results suggest that in addition to the well known systemic effects of the RAS, there are interactions of its components inside the kidney. These interactions may lead to the generation of an extra portion of ANG II in the renal blood stream with its target cells determined by the localization of CE at the luminal side of well defined endothelial areas. These intrarenal-intravasal reactions may or may not reinforce the action of systemic ANG II, generated prerenally. In addition, the existence of true intrarenal-interstitial interactions, with the different components and actions of this intrarenal RAS restricted entirely to the kidney is suggested by our results, particularly the demonstration of ANG II within epitheloid cells and the dissociation of systemic renin and ANG II from their local concentrations in renal hypertensive rats.Supported by the German Research Foundation within the SFB 90 Cardiovasculäres System     

血管紧张素原基因多态性与冠脉狭窄分析

目的　探讨中原地区人群血管紧张素原 (AGT)基因M2 3 5T多态性分布特点与冠心病及冠状动脉狭窄严重程度的关系。方法　采用聚合酶链反应 -限制性片段长度多态性 (PCR -RFLP)技术检测 12 0例冠心病患者和 80例健康对照者AGT基因多态性。对冠心病组所有患者进行冠状动脉造影 ,判定冠脉病变支数 (狭窄程度≥ 75 % )和危险记分。结果　冠心病组TT基因型频率及T等位基因频率与对照组比较差异无显著性 (P >0 .0 5 ) ,分别为 4 0 .9%、31.2 %和 6 6 %、5 7% ,AGT三种基因型间冠脉病变支数和冠脉危险记分差异也无显著性(P >0 .0 5 )。结论　AGT基因M2 3 5T多态性与冠心病的发生和冠脉狭窄严重程度均无相关性     

血清血管紧张素转换酶和血管紧张素原水平与妊娠高血压综合征的相关性及其危险因素

目的 探讨血清中血管紧张素转换酶(ACE)和血管紧张素原 (AGT)与妊娠期高血压综合征（HDCP）的相关性及HDCP发病的危险因素。 方法 选择135例妊娠高血压患者（HDCP组）和100例正常孕妇（CK组）,用ELISA法检测各组的血清ACE、AGT水平,并进行相关性分析;抽取两组孕产妇的年龄、怀孕天数、孕前体质量指数（BMI）、产次、产检次数、高血压糖尿病家族史、文化程度等一般资料,对孕产妇患HDCP的危险因素进行单因素分析,将单因素回归分析中有统计学意义的因素进行多因素 Logistic 回归分析。 结果 HDCP组血清ACE水平（90.49±47.65）μg/L明显高于CK组（58.72±27.58）μg/L,P<0.05,差异有统计学意义;HDCP组血清AGT水平（64.57±19.71）μg/L高于CK组（58.22±18.64）μg/L,P>0.05,差异无统计学意义;单因素分析结果显示,年龄、BMI、高血压、糖尿病家族史、ACE水平是孕产妇患HDCP的危险因素（P<0.05）,怀孕天数、产次、产检次数、文化程度比较差异无统计学意义（P>0.05）;多因素分析显示：年龄、BMI、高血压糖尿病史、ACE水平是妊娠性高血压的危险因素。 结论 ACE水平与HDCP有关,AGT水平与HDCP无关;年龄大、BMI值高、有高血压糖尿病史者,ACE水平增高发生妊娠高血压综合征的风险增加。     

血管紧张素转换酶基因、血管紧张素原基因M235T变异与高原肺水肿的关系

目的     

血管紧张素转换酶及血管紧张素原基因多态性与高血压左室肥厚的相关研究

目的探讨血管紧张素转换酶(ACE)基因插入/缺失(I/D)多态性及血管紧张素原(AGT)基因M235T多态性与高血压左室肥厚(LVH)的关系。方法对68例超声心动图诊断的未接受治疗的高血压合并LVH患者与76例高血压非LVH患者进行病例对照研究。采用聚合酶链式反应(PCR)与限制性片段长度多态性(RFLP)技术检测ACE基因I/D多态性及AGT基因M235T变异。以二维引导的M型超声心动图测量并计算左室重量。结果①该组高血压患者ACE与AGT基因型的分布均符合Hardy Weinberg平衡。②ACE基因I/D基因型在LVH组与非LVH组的分布差异有显著性(χ2=6.777,P<0.05)。LVH组DD基因型与D等位基因的频率均高于非LVH组(DD基因型:0.31vs0.13,χ2=6.674,P=0.01;D等位基因:0.54vs0.41,χ2=4.837,P<0.05)。③AGT基因M235T基因型在LVH组与非LVH组的分布差异有显著性(χ2=7.133,P<0.05)。LVH组TT基因型与T235等位基因的频率均高于非LVH组(TT基因型:0.62vs0.40,χ2=7.133,P<0.01;T235等位基因:0.78vs0.65,χ2=5.741,P<0.05)。④联合基因分析显示,LVH组ACE DD+AGT TT基因型频率显著高于非LVH组(0.22vs0.05,χ2=8.839,P<0.01),具有该联合基因型者发生LVH的风险比数比(OR=5.094)明显高于单独具有ACE DD基因型(OR=2.949)或AGT TT基因型(OR=2.477)者。结论ACE