Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physiological and ligand binding studies have shown that Angiotensin II (AII) exerts various functions along different segments of the nephron, via the type-1 receptor (AT1R), resulting in the control of glomerular filtration rate (GFR) and water and salt homeostasis. We have used the recently cloned AT1R cDNA to localize, by in situ hybridization, the cells expressing AT1R mRNA in the rat kidney. On serial sections, juxtaglomerular (JG) renin secreting cells, identified by hybridization with a renin cRNA probe, also co-express AT1R mRNA. The co-expression of AT1R and renin mRNAs in the same cells documents visually the direct feedback control of AII on renin secretion. AT1R mRNA was also present in known target cells for AII: proximal convoluted tubule, mesangium and vasa recta.
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PMID:Co-expression of type 1 angiotensin II receptor (AT1R) and renin mRNAs in juxtaglomerular cells of the rat kidney. 850 72

Activation of the renin-angiotensin system both systemically and locally seems to be of importance for cardiovascular hypertrophy and remodelling. The octapeptide angiotensin II definitively plays a central role. In the reversal, for example, of left ventricular hypertrophy, so far the most important independent risk factor for an adverse outcome, blocking of the renin-angiotensin system with ACE inhibition has been shown to be particularly effective. In cardiac tissue, however, ACE inhibition has been suggested to inhibit only a fraction of angiotensin II formed, indicating that other enzymatic pathways can be of importance. From a theoretical point of view a more complete blockade of the angiotensin II type 1 receptor would offer a more effective attenuation of the unfavourable effect of angiotensin II. Experimentally, losartan, a novel selective angiotensin II receptor type 1 antagonist has been shown to decrease cardiac hypertrophic response in models of both hypertension and volume cardiac hypertrophy as well as reverse hypertrophy in spontaneously hypertensive rats. TCV-116, another selective angiotensin II antagonist, also effectively reverses cardiac hypertophy and interstitial fibrosis in the rat. The only report so far regarding the effect of angiotensin II blockade on cardiac hypertrophy in essential hypertension suggests a more favourable short-term effect on cardiac hypertrophy for the same blood pressure reduction with losartan compared with atenolol in a small population of mild to moderate hypertensives. In the perspective of the well-established positive effects of ACE inhibition on the remodelling process in the remaining viable myocardium after myocardial infarction, involving myocyte hypertrophy, interstitial fibrosis and progressive dilatation, it is reassuring that angiotensin II blockade has been shown to perform equally well as ACE inhibition after experimental coronary ligation. In summary, the development of cardiovascular hypertrophy in hypertension is a serious prognostic indicator and selective angiotensin II blockade is a new anti-hypertensive treatment modality with promising properties, especially for prevention and reversal of cardiac hypertrophy including pathological fibrosis and cardiac remodelling after myocardial infarction. Thus, taking into account the shortcomings of today's anti-hypertensive treatment to achieve normalisation of excessive cardiovascular morbidity and mortality, as well as the seemingly great importance of the renin-angiotensin system for hypertension-induced functional and structural abnormalities, a therapy based on a specific All antagonist could offer obvious advantages in a high risk hypertensive patient with cardiovascular hypertrophy. This hypothesis will be investigated in a large prospective trial (Losartan Intervention For End-point reduction in hypertension: The LIFE Study).
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PMID:Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review. 858 80

The renin-angiotensin system plays a crucial role in the development and establishment of the hypertensive state in the spontaneously hypertensive (SH) rat. Interruption of this system's activity by pharmacological means results in the lowering of blood pressure (BP) and control of hypertension. However, such means are temporary and require the continuous use of drugs for the control of this pathophysiological state. Our objective in this investigation was to determine if a virally mediated gene-transfer approach using angiotensin type 1 receptor antisense (AT1R-AS) could be used to control hypertension on a long-term basis in the SH rat model of human essential hypertension. Injection of viral particles containing AT1R-AS (LNSV-AT1R-AS) in 5-day-old rats resulted in a lowering of BP exclusively in the SH rat and not in the Wistar Kyoto normotensive control. A maximal anti-hypertensive response of 33 +/- 5 mmHg was observed, was maintained throughout development, and still persisted 3 months after administration of LNSV-AT1R-AS. The lowering of BP was associated with the expression of AT1R-AS transcript and decreases in AT1-receptor in many peripheral angiotensin II target tissues such as mesenteric artery, adrenal gland, heart, and kidney. Attenuation of angiotensin II-stimulated physiological actions such as contraction of aortic rings and increase in BP was also observed in the LNSV-AT1R-AS-treated SH rat. These observations show that a single injection of LNSV-AT1R-AS normalizes BP in the SH rat on a long-term basis. They suggest that such a gene-transfer strategy can be successfully used to control the development of hypertension on a permanent basis.
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PMID:Chronic control of high blood pressure in the spontaneously hypertensive rat by delivery of angiotensin type 1 receptor antisense. 879 Apr 39

Most of the biological effects of the renin-angiotensin system are mediated by the binding of angiotensin II (Ang II) to the type 1 Ang II (AT1) receptor, the predominant receptor subtype present after fetal life. To study tissue-specific regulation of the expression of the AT1 receptor in the rat, we altered activity of the renin-angiotensin system by feeding rats a low (0.07% NaCl), normal (0.3% NaCl), or high (7.5% NaCl) salt chow for 14 days; infusing Ang II (200 ng/kg per minute IP) or vehicle for 7 days; and administering an angiotensin-converting enzyme inhibitor (captopril, 100 mg/dL in the drinking water) or vehicle for 7 days. Renin, angiotensinogen, and total AT1 receptor mRNA levels were measured by slot-blot hybridization with cRNA probes, and AT1 receptor subtypes (A and B) were measured by reverse transcription-polymerase chain reaction in the presence of a cRNA internal standard. Plasma renin concentration and renal renin, renal and hepatic angiotensinogen, and hepatic AT1 receptor mRNA levels were all inversely related to salt intake; in contrast, renal AT1 receptor mRNA levels were significantly lower in rats fed low salt, a difference that was exclusively due to a decrease in the AT1A subtype. This difference did not appear to be mediated by a change in the circulating levels of Ang II, because Ang II infusion reduced plasma renin concentration and renal renin mRNA with no effect on either angiotensinogen or AT1 receptor mRNA levels in kidney or liver, renal Ang II receptor density (determined by in situ autoradiography) decreased, presumably via a posttranscriptional mechanism. Similarly, inhibition of Ang II generation with captopril increased plasma renin concentration and renal renin mRNA levels without altering renal or hepatic angiotensinogen mRNA or renal AT1 receptor mRNA levels. Thus, AT1 receptor gene expression is regulated in a tissue-specific manner that is distinct from other components of systemic and local renin-angiotensin systems and that appears to be mediated by a mechanism other than through changes in the circulating levels of Ang II.
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PMID:Tissue-specific regulation of type 1 angiotensin II receptor mRNA levels in the rat. 879 24

Although it is well known that mechanical load to cardiac muscles causes cardiac hypertrophy, little is known about how mechanical load is transduced into the activation of intracellular signals which are linked to cell growth. We investigated whether the cardiac renin-angiotensin system was involved in stretch-induced hypertrophy of cultured neonatal rat heart myocytes. Myocytes were cultured with serum-free medium in a deformable silicon dish. Stretch of cardiac myocytes significantly increased the protein/DNA ratio at culture days 6 and 7, and the RNA/DNA ratio at culture days 4 and 5. Stretch significantly accelerated rates of protein synthesis by 15%. c-fos mRNA expression was significantly increased after stretch. The stimulatory effects of cell stretch on these parameters were significantly inhibited by the angiotensin converting enzyme inhibitor, captopril, or the type 1 angiotensin II receptor antagonist, losartan. The concentrations of angiotensin I and angiotensin II in culture media were significantly increased by stretch. Stretch did not change the angiotensin converting enzyme activity. These studies demonstrate that mechanical stretch activates the cardiac renin-angiotensin system in a autocrine and paracrine system which acts as an initial mediator of the stretch-induced hypertrophic growth.
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PMID:Renin-angiotensin system in stretch-induced hypertrophy of cultured neonatal rat heart cells. 883 Nov 8

The effects of dietary sodium intake on the gene expression of the renin-angiotensin system (RAS) were investigated in rat central and peripheral tissues in a single set of experiment. Northern and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques were used to detect mRNA expression in rats fed a low- or a high-sodium diet (5 or 500 mmol Na+/kg diet) for 20 days. Plasma and renal renin levels were elevated in rats maintained on the low-sodium diet. Sodium deprivation enhanced the expression of angiotensinogen, renin, AT1A and AT1B receptor subtypes in the hypothalamus, but suppressed them in the brainstem. Kidney and adrenal levels of those mRNAs were also enhanced in the sodium-restricted rats. Both AT1A and AT1B mRNAs changed in a similar magnitude in each tissue examined upon dietary sodium intake. AT1A was the predominant receptor subtype of AT1 in all the tissues examined in the present study except the adrenal gland. The present study demonstrated that dietary sodium modulated the gene expression of the RAS components in the central and peripheral tissues. It also showed that the RAS components in the brainstem and hypothalamus were differentially expressed upon sodium deprivation. This suggests different roles of the RAS in these tissues in maintaining body fluid homeostasis in response to different sodium intakes.
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PMID:Gene expression of central and peripheral renin-angiotensin system components upon dietary sodium intake in rats. 895 82

To elucidate the signal transduction pathway from external stimuli to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of protein kinases such as Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) in neonatal rat cardiomyocytes. Mechanical stretch rapidly activated Raf-1 and its maximal activation was observed at 1-2 min after stretch. The activity of MAPKK was also increased by stretch, with a peak at 5 min after stretch. In addition, MAPKs and p90rsk were maximally activated at 8 min and at 10-30 min after stretch, respectively. Next, the relationship between mechanical stress-induced hypertrophy and the cardiac renin-angiotensin system was investigated. When the stretch-conditioned culture medium was transferred to the culture dish of non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type 1 angiotensin II receptor antagonist, CV-11974. However, activation of Raf-1 and MAPKs provoked by stretching cardiomyocytes was only partially suppressed by pretreatment with CV-11974. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK, MAPKs and p90rsk, and that angiotensin II, which is secreted from stretched myocytes, activates a part of these protein kinases.
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PMID:Molecular aspects of mechanical stress-induced cardiac hypertrophy. 897 57

Genetic polymorphisms of the renin-angiotensin system (RAS) have been associated with coronary artery disease (CAD) but no relation between these polymorphisms and coronary atherosclerosis has yet been systematically evaluated. The CORGENE study is a cross-sectional study involving 463 Caucasians who underwent standardized coronary angiography for established or suspected CAD [156 patients with a previous myocardial infarction (MI), 307 without MI]. Four angiographic scores assessing the extent and severity of the coronary lesions were obtained from a double visual analysis of each angiogram, arbitration being achieved by a quantitative measurement. Three different genotypes were analyzed: the angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism, the Met to Thr change at position 235 of the angiotensinogen gene (AGT M235T) and the A to C transition at position 1166 of the angiotensin II type-1 receptor gene (AT1R A1166C). No significant association was observed between these polymorphisms and the clinical characteristics of MI and non-MI subjects. While most classical risk factors were positively correlated with the angiographic scores, no significant relationship could be established with the three genotypes (r ranging from -0.08 to 0.05). Only one significant correlation was observed: between the presence of the AGT 235T allele and the extent of the coronary lesions (r = -0.19, P = 0.04) in patients with low-risk status. These overall results are not in favor of a role of these RAS genetic polymorphisms in the development of coronary atherosclerosis.
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PMID:Genetic polymorphisms of the renin-angiotensin system and angiographic extent and severity of coronary artery disease: the CORGENE study. 900 97

The combination of single oral doses of an angiotensin I-converting enzyme inhibitor (captopril) and a type 1 angiotensin II receptor antagonist (losartan) has additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. We planned the present study to determine whether the magnitude of the hemodynamic and hormonal consequences of renin-angiotensin system blockade by such a combination is larger than that obtained by doubling the dose of the angiotensin-converting enzyme inhibitor given alone. In a single-dose, double-blind, randomized, three-way crossover study, 10 mg enalapril, 20 mg enalapril, and the combination of 50 mg losartan and 10 mg enalapril were administered orally to 12 sodium-depleted normotensive subjects. The area under the time curve from 0 to 24 hours (AUC0-24) of the mean blood pressure fall after losartan-enalapril combination intake (-220 +/- 91 mm Hg.h) was significantly greater than that of either 10 or 20 mg enalapril (-124 +/- 91 and -149 +/- 85 mm Hg.h, respectively, P < .05 vs both doses). The combination significantly increased by 2.3 +/- 1.2-fold the AUC0-24 of plasma active renin compared with either 10 or 20 mg enalapril given alone (P < .05) but had no additive effect on plasma aldosterone fall. The losartan-enalapril combination is more effective in decreasing blood pressure and increasing plasma active renin than doubling of the enalapril dose.
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PMID:Additive effects of losartan and enalapril on blood pressure and plasma active renin. 904 Apr 50

Low sodium intake has been demonstrated to upregulate the gene expression of the predominant renal type 1 angiotensin II (Ang II) receptor (AT1), the AT1A subtype. The study presented here tests the hypothesis that the upregulation of renal AT1 mRNA induced by sodium depletion occurs conjointly with an elevation of the AT1 receptor that modulates renal growth. Seven-week-old male Wistar rats were divided into four groups and treated for 2 wk with normal sodium diet, normal sodium diet plus 3 mg/kg/day losartan, low sodium diet, or low sodium diet plus losartan. Body weight and MAP were not significantly different among the four groups. Plasma renin activity was significantly elevated by losartan treatment, low salt intake, or a combination of the two, compared with the plasma renin activity of the controls. Northern blot analysis indicated that renal AT1 mRNA levels were significantly increased-183% by losartan, 212% by low salt intake, and 227% by the combination of the two-compared with their levels in controls. Radioligand binding assays revealed that AT1 receptors were significantly increased by low salt intake but were significantly decreased by losartan treatment. Renal AT1 receptor binding in the rats subjected to sodium depletion plus losartan did not differ from that in control rats. Kidney weight, kidney weight/body weight ratio, and renal DNA and protein content were not altered by sodium depletion but were significantly lowered by losartan treatment with both normal and low sodium intake, compared with those of controls. The protein/DNA ratio was not significantly different among the four groups. Blockade of renal AT1 receptors with losartan was found to retard normal renal growth, indicating that Ang II is required for normal renal development. Low sodium intake was found to increase mRNA and expression of the renal AT1 receptor but to have no effect on renal growth, suggesting that an increase in renal mass above a normal level requires the activation of multiple factors. Blockade of the AT1 receptor by losartan was found to upregulate AT1 mRNA but to down-regulate the AT1 receptor, suggesting that AT1 receptor-mediated intracellular events are necessary to sustain functional AT1 receptor expression in the kidney.
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PMID:Regulation of angiotensin type 1 receptor and its gene expression: role in renal growth. 904 37


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