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)

Renin is one of the most important factors in blood pressure and electrolyte regulation in mammals and the renin locus has been implicated in hypertension. To assist studies of promoter control we therefore determined the 5'-flanking sequence of the human gene (REN) to residue -2750 relative to the transcription start site (+1). Sites of homology to consensus sequences for binding of trans-acting factors involved in transcriptional control of other genes were identified, and functionality for two of these (a CRE and Pit-1 site) have so far been demonstrated.
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PMID:Human renin 5'-flanking DNA to nucleotide-2750. 757 88

An understanding of the mechanisms involved in the control of the human renin promoter have been hampered and confounded in work to date because of deficiencies in material available and experimental design. The promoter appears to be weak and a good cell model is lacking. Chorio-decidual cultures have been used since these have high renin synthesis, are readily available and grow well in culture. They suffer, however, from phenotypic variability and do not transfect well in transient expression analyses. Recent evidence suggests that 2.6 kb of proximal 5'-flanking DNA is unable to induce native promoter activity under basal conditions. Experiments in which an exogenous enhancer was introduced have raised the possibility that an endogenous enhancer residing outside of the 2.6 kb 5'-flanking region could be required. Cell-type specific factors also appear to be needed. The proximal flanking DNA does, however, appear to be capable of conferring activity on the promoter in chorio-decidual cells under stimulated conditions, suggesting that factors so activated may have considerable importance. Evidence suggests that forskolin-responsive signal transduction pathways may lead cyclic AMP responsive element (CRE) binding protein (CREB) to act on a CRE at -222 in the proximal REN promoter DNA. Activation of the mouse promoter by cAMP appears to involve a different element, however. Furthermore, overall control of renin synthesis is likely to involve post-transcriptional mechanisms as well. Thus, despite being the first cardiovascular gene to be cloned, much more work is required before the control of the human renin gene is fully understood.
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PMID:Function of human renin proximal promoter DNA. 769 94

The link between hyperinsulinemia and hypertension is imperfectly understood. Recently, a renin gene (the mouse DBA/REN-2d gene) has been transfected into rats, leading to high blood pressure in transgene-positive animals, TGR(mREN-2)27 rats. We tested whether heterozygous hypertensive TGR(mREN-2)27 rats presented evidence of insulin resistance in comparison with the parent strain of Sprague-Dawley rats. Despite their higher blood pressure (203 +/- 8 vs. 112 +/- 6 mmHg, P < 0.001), transgenic rats had normal fasting levels of plasma glucose, insulin, free fatty acids, and triglycerides and had normal fasting rates of hepatic glucose production (by [14C]glucose infusion). During a euglycemic hyperinsulinemic clamp (3 mU/min), stimulation of whole body glucose utilization was equivalent in transgenic and control animals (12.6 +/- 0.6 vs. 10.9 +/- 1.0 mg.min-1.kg-1, respectively). Likewise, suppression of hepatic glucose output by insulin was complete in both groups. The glucose utilization index (as measured by the 2-deoxy-D-[3H]glucose technique) was similar between transgenic and control animals in several skeletal muscles (soleus, extensor digitorum longus, tibialis, diaphragm, white and red quadriceps, and white and red gastrocnemius), in white adipose tissue (periovarian and inguinal), and in brown adipose tissue. We conclude that single gene hypertension does not alter whole body and individual tissue insulin sensitivity.
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PMID:Insulin resistance and hypertension: studies in transgenic hypertensive TGR(mREN-2)27 rats. 781 Jul 59

Transgenic animals are used to study the function, regulation and in vivo expression of genes. The effects of the genes of the renin-angiotensin system on blood pressure regulation and hypertension were invested in transgenic rats. The role of the renin-angiotensin system in the development of the cardiovascular hypertrophy or hypertensive renal damage was analysed, as well as its interaction with other hormonal systems, i.e., adrenal steroids. The development of a transgenic rat strain carrying the mouse REN-2 gene has provided a new model of hypertension with systolic blood pressure values of 200 mmHg. This model is characterised by low active plasma renin, hyperproreninaemia and high expression of renin in the adrenal gland and other external tissues. Transgenic rats with the human components of the renin-angiotensin system expressed the human renin and angiotensinogen proteins which interacted species-specifically in transgenic rats. These transgenic models demonstrate the feasibility of studying the function of candidate hypertension genes in transgenic animals. In the future, further refinements in transgene construction, mutation, and modification can be tested in such transgenic animal models.
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PMID:The renin-angiotensin system in transgenic rats. 861 36

The effect of acute plasma volume change in humans on serum erythropoietin [EPO]s, plasma active renin [REN] and plasma aldosterone [ALDO] concentrations was examined. Plasma volume (PV) expansion was induced by intravenous infusion of 150 ml (30g) of plasma albumin and 500 ml of physiological saline. The [EPO]s decreased by 14.3% (corrected values for PV expansion) and remained decreased for 5 h. The [REN] was decreased by more than 25% during the day of the experiment and [ALDO] by more than 60%. Only a weak positive correlation was found between [EPO]s and [REN] (r = 0.35; P < 0.05) but a lack of correlation between changes in PV and [EPO]s as well as between [EPO]s and [ALDO] was seen. We postulated that in healthy men an acute PV expansion by 10% to 17.5% would not appear to promote stimulation of EPO synthesis for at least 11 h. Since a weak positive correlation was observed between [EPO]s and [REN] and a lack of correlation between [EPO]s and [ALDO], it would seem that there is no direct link between [REN] and [ALDO] and erythropoietin synthesis in healthy subjects.
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PMID:An early effect of acute plasma volume expansion in humans on serum erythropoietin concentration. 878 79

Gene coding for the main components of the renin-angiotensin system have been characterized and localized: angiotensinogen (AGT, chromosome 1q42), renin (REN, chromosome 1), angiotensin I-converting enzyme (ACE, chromosome 17), angiotensin II receptors (AT1R, chromosome 3 and AT2R, chromosome X). A positive linkage and association have been found between AGT and essential hypertension. M235T is also associated with plasma AGT concentration. In vitro studies suggest that a polymorphism (G-6A) which is in complete linkage disequilibrium with M235T and which is located in the promoter close to the start of transcription might explain this association with high blood pressure. The ACE I/D polymorphism explains about 30 to 40 per cent of the variance of plasma ACE levels. Although the ACE gene itself does not seem to play a role in blood pressure level, the corresponding chromosomal region has been linked to blood pressure in both spontaneously hypertensive rats and humans. In tissues, an increased ACE activity may explain the association between the ACE I/D polymorphism and coronary heart disease, left ventricular hypertrophy, neointimal proliferation in vessels and progression of diabetic and IgA nephropathy.
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PMID:[Genetic polymorphisms in the renin-angiotensin system]. 977 26

Renal scarring with and without vesicoureteral reflux (VUR) has been now recognized as an important cause of paediatric hypertension for many years [1-5]. However, its pathogenesis has still remained uncleared. The widespread concept implicated the activation of renin-angiotensin system finding a powerfull support in higher peripheral plasma renin activity (PRA) in children with reflux nephropathy than in controls [6, 7] and in beneficial antihypertensive effects of ACE inhibitors. The latter, in form of captopril, has also been used in captopril test and in renal scintigraphy and isotope renography following the administration of captopril to provide evidence for renin dependent hypertension [8, 9]. Published studies of captopril test have centred on the identification of renovascular as opposed to essential hypertension [10-18, 20-22]. The aim of our study was to assess the usefulness of captopril test in differentiation between hypertensive children with renal scarring from those with essential hypertension. We studied blood pressure (BP) and PRA responses to a single dose of captopril in two groups of hypertensive children. Group A consisted of 29 patients, 14 boys and 15 girls, who had renal scaring as demonstrated by renal 99mTc dimercaptosuccinid acid scan (99m Tc DMSA) and/or intravenous pyelography. Group B included 19 patients, 19 boys and 10 girls who had arterial hypertension, while clinical examination excluded renal and other definable causes of BP elevation, and they were therefore considered to have essential hypertension. At the time of the study all patients had normal glomerular filtration rate and were not salt depleted. They did not receive any antihypertensive medication for at least two weeks. The test was performed in the morning in fasting sitting patients. At the start of the test a small vein in the hand or forearm was cannulated to permit blood sampling. BP was measured 10, 20, and 30 minutes before captopril administration to get baseline BP (mean of these three measurements) and to allow the children to become accustomed to the test procedure. A single oral dose of captopril 0.64 +/- 0.04 mg/kg body weight was given to patients from group A and almost the same dose of captopril, 0.63 +/- 0.05 mg/kg body weight, to patients from group B. The patients remained sitting and BP was measured every 15 minutes during an hour. Blood for PRA was drown in the sitting position (17 patients from group A and 16 patients from group B) before and one hour after the dose of captopril. Samples of blood for basal PRA were collected from 16 patients from group A and in 14 patients from in B in lying position after waking up in the morning. PRA was measured by radioimmunoassay using a commercially available kit, SB-REN 2, from CIS Bio International. According to the criteria of Muller et al. [10] the captopril test was positive if the post-captopril PRA (ng/ml/h) was greater than or equal to 12 with an increase of greater than or equal to 10 and relative increase of greater than or equal to 15% (400% if initial PRA was < 3). The results of our study are presented in Tables 1 and 2 and in Graphs 1 and 2. The age of patients, doses of captopril, initial BP and PRA before the use of captopril did not much differ between studied groups. Fall of BP and PRA increase were highly significant (p < 0.001) both in group A and group B. However, the hypotensive reaction of diastolic BP and MAP were more pronounced in group A (14.45 +/- 1.67% and 15.81 +/- 1.62%) than in group B (6.95 +/- 2.21% and 8.96 +/- 1.75%; p < 0.01), but there were no significant differences in PRA and systolic BP changes and positive results of captopril test between the studied groups. Hypotensive responses of diastolic BP and MAP greater than 10% of initial values were found to be more frequent in group A (79.32% and 79.31%) than in group B (26.61% and 31.57 degrees %; p < 0.001 and p < 0.01). Diastolic BP and MAP were directly related to the dose of cap
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PMID:[The captopril test--an aid in the detection of scarring nephropathy as a cause of arterial hypertension in children]. 1064 99

The renin angiotensin system (RAS) is involved in blood pressure control and water/sodium metabolism. The genes encoding the proteins of this system are candidate genes for essential hypertension. The RAS involves four main molecules: angiotensinogen, renin, angiotensin I-converting enzyme, and the angiotensin II type 1 receptor (encoded by the genes AGT, REN, DCP1, and AGTR1, respectively). We performed a molecular screening over 17,037 bp of the coding and 5' and 3' untranslated regions of these genes, from three to six common chimpanzees. We identified 44 single-nucleotide polymorphisms (SNPs) in chimpanzee samples, including 18 coding-region SNPs, 5 of which led to an amino acid replacement. We observed common and different features at various sites (synonymous, nonsynonymous, and noncoding) within and between the four chimpanzee genes: (1) the nucleotide diversity at noncoding sites was similar; (2) the nucleotide diversity at nonsynonymous sites was low, probably reflecting purifying selection, except for the AGT gene; (3) the nucleotide diversity at synonymous sites, which was dependent on the G+C content at the third position of the codon, was high, except for the AGTR1 gene. Comparison of the chimpanzee SNPs with those previously reported for humans identified 119 sites with fixed differences (including 62 coding sites, 17 of which resulted in amino acid differences between the species). Analysis of polymorphism within species and divergence between species shed light on the evolutionary constraints on these genes. In particular, comparison of the pattern of mutation at polymorphic and fixed sites between humans and chimpanzees suggested that the high G+C content of the DCP1 gene was maintained by positive selection at its silent sites. Finally, we propose 68 ancestral alleles for the human RAS genes and discuss the implications for their use in future hypertension-susceptibility association studies.
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PMID:Human-chimpanzee DNA sequence variation in the four major genes of the renin angiotensin system. 1101 71

We previously reported the generation of 2 novel transgenic mouse models containing the human renin (hREN) gene encoded on P1 artificial chromosomes (PAC) containing large amounts of 5'-flanking DNA. These mice exhibit a very narrow tissue-specific expression profile and exhibit tightly regulated expression in kidney in response to physiological cues. In brain, transcription of hREN occurs from an alternative upstream promoter, causing translation to initiate within exon-II and potentially generating an intracellular form of active renin. Double transgenic mice containing a PAC transgene and the human angiotensinogen (hAGT) gene (P+/A+) are moderately hypertensive. We tested whether increased RAS activity in the brain contributes to the mechanism of hypertension in P+/A+ double transgenic mice. Expression of hREN mRNA in brain was confirmed in 4 independent PAC transgenic lines and utilization of the alternative transcription start site in brain was confirmed in each line. Human REN immunostaining was observed in the dorsal cochlear nucleus, hypothalamus, and cortex. P+/A+ mice exhibited a greater fall in mean arterial pressure after intracerebroventricular injection of losartan than controls. P+/A+ mice exhibited a greater drop in arterial pressure after intravenous injection of a vasopressin V(1) receptor antagonist, and an equivalent drop in arterial pressure after intravenous injection of a ganglion blocker compared with controls. These results support the hypothesis that renin is endogenously expressed in the brain and suggest that increased brain RAS activity may contribute to the maintenance of moderate hypertension in P+/A+ transgenic mice at least in part by a vasopressin-dependent mechanism.
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PMID:The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene. 1178 10

The brain renin-angiotensin system (RAS) has an important role in the regulation of cardiovascular function. In the brain, angiotensinogen (AGT) is expressed mainly in astrocytes (glia) and in some neurons in regions controlling cardiovascular activities. Because of the inability to dissect the functional role of astrocyte- vs. neuron-derived AGT in vivo by pharmacological approaches, the exact role of neuron-derived AGT in the regulation of blood pressure (BP) and fluid and electrolyte balance remains unclear. Therefore, we generated a transgenic mouse model overexpressing human AGT under the control of a neuron-specific (synapsin I) promoter (SYN-hAGT). These mice exhibited high-level expression of human AGT mRNA in the brain, with lower expression in the kidney and heart. Human AGT was not detected in plasma, but in the brain it was expressed exclusively in neurons. Intracerebroventricular (30 ng) but not intravenous (500 ng) injection of purified human renin (hREN) caused a pressor response, which was prevented by intracerebroventricular preinjection of the angiotensin II type 1 receptor antagonist losartan, indicating an AT(1) receptor-dependent functional role of neuron-derived AGT in the regulation of BP in response to exogenous REN. Double transgenic mice expressing both the hREN gene and SYN-hAGT transgene exhibited normal BP and water intake but had an increased preference for salt. These data suggest that neuronal AGT may play an important role in regulating salt intake and salt appetite.
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PMID:Neuron-specific expression of human angiotensinogen in brain causes increased salt appetite. 1200 77


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