Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ren-1 locus of mice encodes the protease renin, which with converting enzyme processes angiotensinogen to the potent vasopressor angiotensin II. Some strains of mice appear to carry a duplication of the renin structural gene (Ren-2) near the Ren-1 locus. Strains with the gene duplication can exhibit as much as 100-fold higher levels of submaxillary gland renin compared to strains with a single gene copy. In contrast, kidney renin levels appear to be unaffected by the gene duplication. Sequence analysis of a 319 bp renin cDNA recombinant isolated from a kidney library from the two-gene strain DBA/2Ha corresponds to a transcript of the Ren-1 gene. Moreover, a single base substitution of A for G at residue #996 in the kidney renin mRNA creates a potential glycosylation recognition site that may, in part, account for the differential glycosylation of kidney and submaxillary gland renins. In addition, our tissue surveys indicate that mature mRNAs from the Ren loci are detectable in adrenal gland and testes, as well as sublingual and parotid salivary glands, and reveal length variation for the renin transcripts in at least the submaxillary gland.
Hypertension
PMID:Tissue and gene specificity of mouse renin expression. 637 91

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.
 ...
PMID:Insulin resistance and hypertension: studies in transgenic hypertensive TGR(mREN-2)27 rats. 781 Jul 59

The transgenic rat TGR(mRen-2)27, in which the Ren-2 mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouse Ren-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4 +/- 37.3 ng angiotensin I/mL, n = 4). The reaction of purified mouse Ren-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from 253.4 +/- 66.7 to 225,000 +/- 48,000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 microL of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7 +/- 4.7 and 61.8 +/- 2.7 mmHg, respectively, whereas injection of 200 microL of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Apr
PMID:Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen. 814 11

TGR(mREN2)27 is a new monogenetic rat model with fulminant hypertension, low kidney renin, and high extrarenal renin gene expression. This study characterizes and compares expression of the Ren-2 gene in TGR(mREN2)27 with that in DBA/2 mice and with renin gene expression in rats. Except in the submandibular gland, the tissue-specific expression of Ren-2 is similar in TGR(mREN2)27 and DBA/2. This demonstrates maintenance of tissue specificity. Organs that are involved in cardiovascular regulation, such as the adrenal gland, kidney, and brain, express the Ren-2 gene before hypertension has developed, consistent with the possibility of a causal relationship between transgene expression in these tissues and hypertension. Because these tissues express the renin gene in nontransgenic rats as well, we suggest that this model can be used to study the regulation of renin gene expression and its role in hypertension at these sites. In addition, as an indication that interactions may exist between blood pressure and renin gene expression, we describe reciprocal changes in blood pressure and Ren-2 mRNA levels in the kidney and brain.
 ...
PMID:Ontogenetic regulation of mouse Ren-2d renin gene in transgenic hypertensive rats, TGR(mREN2)27. 823 95

Primary human hypertension is a polygenic disorder. It is the prevalent cause of cardiovascular disease leading to cardiac failure, stroke, chronic renal failure and, ultimately to death. Several genes are involved in cardiovascular control mechanisms and their genetics are complex. Experimental models which are well defined are needed to clarify the role of individual genes. The generation of the hypertensive transgenic rat line TGR (mREN2)27 bearing the murine Ren-2 gene cloned from the DBA/2J mouse strain provides a monogenic model of hypertension in which the genetic basis (the additional renin gene) is known. These rats develop severe hypertension, which reaches 200 mm Hg and higher at 8 weeks of age in the heterozygous animal. Homozygous rats develop even higher blood pressures than heterozygous animals, which is paralleled by a higher mortality rate in homozygous rats. Animals develop pathomorphologic alterations which are characteristic for systemic hypertension. The transgenic rats are characterized by unchanged or even suppressed concentrations of active renin, angiotensin I (ANG I), ANG II, and angiotensinogen compared to transgene-negative littermates. In contrast, plasma levels of inactive renin (prorenin) are much higher in TGR (mREN)27 rats than in control animals. In the kidneys, renin is suppressed, probably mediated through negative feedback inhibition, in other tissues, especially in the adrenal gland, murine Ren-2 mRNA is expressed at very high levels. The cascade of pathophysiologic events which finally lead to hypertension is not fully understood in this rat model. Treatment with ACE inhibitors or angiotensin II receptor antagonists such as losartan is extremely efficient, which could mean that hypertension in this model is mediated through ANG II. Since the the renin-angiotensin system (RAS) in the kidneys is suppressed, other ANG II generating sites must be considered. This favors the concept of extrarenal RASs in this model.
 ...
PMID:The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects. 873 83

-We have used comparative sequence analysis to evaluate a putative silencer element that has been proposed to be involved in the differential tissue-expression of the murine renin genes: Ren-1 and Ren-2. In the mouse, these genes share a similar pattern of tissue-specific renin expression. One significant difference is seen in the submandibular gland (SMG) where renin expression from the Ren-2 locus is 100-fold greater than the expression from the Ren-1 locus. One model proposes that this differential expression arises from the interplay among a negative regulatory element and a cAMP responsive element, their respective binding factors, and the disruption of the negative regulatory element by an insertion (M2) that is found in Ren-2 but not in Ren-1. The abrogation of the negative regulatory element's function as a result of the M2 insertion was proposed to be specifically responsible for the higher level of Ren-2 expression in the SMG as compared with Ren-1. We have assessed this hypothesis by looking at an allelic variant in the closely related mouse species M. hortulanus. This species shares the same high level of Ren-2 expression in the SMG as seen in other Ren-2 positive mouse strains. However, the Ren-2 M. hortulanus allele does not appear to contain the disruptive M2 element according to restriction-enzyme mapping. Our sequence analysis confirms that the M. hortulanus Ren-2 allele contains the same sequence elements present in the DBA/2 Ren-2 allele except for the M2 element. Moreover, the proposed negative regulatory element is intact at the sequence level in Ren-2 M. hortulanus allele. This analysis suggests that any involvement of the negative regulatory element in differential Ren-1 and Ren-2 expression in the SMG is not as straightforward as previously hypothesized.
Hypertension 2001 Jan
PMID:Evaluating a Model of an NRE Mediated Tissue-Specific Expression of Murine Renin Genes. 1120 64

The impact of genetic variation on cardiovascular responses to hypoxia and hypercapnia is not well understood. Therefore, we determined the acute changes in systemic arterial blood pressure (P(SA)) and heart rate (HR) in seven strains of commonly used inbred mice exposed to acute periods of hypoxia (10% O(2)), hypercapnia (5% CO(2)), and hypoxia/hypercapnia (10% O(2) + 5% CO(2)) during wakefulness. Hypercapnia induced an essentially homogeneous response across strains, with P(SA) maintained at or slightly above baseline and with HR exhibiting a typical baroreceptor-mediated bradycardia. In contrast, exposure to hypoxia elicited a marked heterogeneity in cardiovascular responses between strains. The change in P(SA) during hypoxia ranged from maintenance of normotension in the FVB/J strain to profound hypotension of approximately 30 mmHg in the DBA/2J strain. HR responses were highly variable between strains during hypoxia, and with the exception of the DBA/2J strain that exhibited significant bradyarrhythmias and consequent hypotension, the HR responses were unrelated to changes in P(SA). The P(SA) response to combined hypoxia/hypercapnia represented a balance of the hypertension of hypercapnia and the hypotension of hypoxia in six of the seven strains. In the FVB/J strain, combined hypoxia/hypercapnia produced a hypertensive response that was greater than that of hypercapnia alone. These results suggest that genetic background affects the cardiovascular response to hypoxia, but not hypercapnia.
 ...
PMID:Phenotypic variation in cardiovascular responses to acute hypoxic and hypercapnic exposure in mice. 1549 73

Thirty males with prior myocardial infarction concurrent with arterial hypertension (AH) were examined to study the antihypertensive and antiischemic effects of the AT1-receptor blocker irbesartran. Group 1 comprised 12 (40%) patients with mild AH; Group 2 included 18 (60%) with moderate AH. In Group 2, the standard therapy with irbesartan in a single dose of 150 mg in the morning was supplemented by the beta1-adrenoblocker atenolol in the average daily dose of 31.25 mg. In Group 1 patients there were decreases in systolic blood pressure (SBP) by 28% and diastolic blood pressure (DBA) by 19% while in Group 2 receiving combined therapy with atenolol, SBP lowered on the average of 38.3 mm Hg of the baseline values and DBA became normal in 66.7% of the patients (p < 0.00). Thus, irbesartan provides good antihypertensive and antiischemic effects in patients with grade 1 AH; the combined therapy enhances the efficiency of treatment by 92% in patients with moderate AH.
 ...
PMID:[Antihypertensive and antiischemic effectiveness and safety of the AT1-receptor blocker irbesartranin arterial hypertension in patients with prior myocardial infarction]. 1573 20

Perinatal growth restriction (PGR) is associated with type 2 diabetes and hypertension. Identification of an isogenic mouse model of fetal programming will facilitate mechanistic understanding. We sought to test the hypotheses that 1) PGR impairs glucose tolerance and induces hypertension; and 2) the programming phenotype is more severe in an inbred mouse strain susceptible to diabetes (C57BL/6) than in a strain without such genetic predisposition (DBA/2). PGR pups were paired at weaning with same sex normally grown littermates. Glucose and insulin tolerance tests were performed at 17 wk, and systolic blood pressure (SBP) was measured at 20 wk. Impaired glucose tolerance was evident only among female PGR mice from both strains. While PGR did not alter insulin sensitivity in either strain, female DBA/2 mice had significantly decreased insulin levels during glucose tolerance testing. SBP was increased in PGR male C57BL/6 mice (p<0.01), while heart rate was decreased in PGR male DBA/2 mice (p<0.05). These studies indicate that in isogenic mice, PGR alters endocrine and cardiovascular physiology in female and male mice, respectively. Strain-and sex-specific genetic susceptibilities emphasize the need to consider genetic predisposition when evaluating the role of the perinatal environmental in the inception of adult disease.
 ...
PMID:Naturally occurring perinatal growth restriction in mice programs cardiovascular and endocrine function in a sex- and strain-dependent manner. 1766 47

Tacrolimus (FK506) is a potent immunosuppressant widely used for organ transplantation patients while diltiazem (DTZ), a calcium-channel inhibitor, is often used in renal transplantation patients to prevent post-transplant hypertension. However, DTZ has a significant pharmacokinetic interaction with FK506. In this study, a rapid and sensitive ammonium-adduct based liquid chromatography-tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the simultaneous determination of FK506 and DTZ in human whole blood using ascomycin as the internal standard (IS). After extraction of the whole blood samples by ethyl acetate, FK506, DTZ and the IS were subjected to LC/MS/MS analysis using electro-spray positive-ion mode ionization (ESI(+)). Chromatographic separation was performed on a Hypersil BDS C18 column (50 mm x 2.1 mm, i.d., 3 microm). The MS/MS detection was conducted by monitoring the fragmentation of 821.7-->768.9 (m/z) for FK506, 415.5-->310.3 (m/z) for DTZ and 809.8-->757.0 (m/z) for IS. The method had a chromatographic running time of approximately 2 min and linear calibration curves over the concentrations of 0.5-200 ng/mL for FK506 and 2-250 ng/mL for DTZ. The recoveries of liquid-liquid extraction method were 58.3-62.6% for FK506 and 50.4-58.8% for DTZ. The lower limit of quantification (LLOQ) of the analytical method was 0.5 ng/mL for FK506 and 2 ng/mL for DTZ. The intra- and inter-day precision was less than 15% for all quality control samples at concentrations of 2, 10, and 50 ng/mL for FK506 and 5, 25, and 100 ng/mL for DTZ. The validated LC/MS/MS method has been successfully used to analyze the concentrations of FK506 and DTZ in whole blood samples from pharmacokinetic studies in renal transplanted patients.
 ...
PMID:Rapid and simultaneous determination of tacrolimus (FK506) and diltiazem in human whole blood by liquid chromatography-tandem mass spectrometry: application to a clinical drug-drug interaction study. 1841 31


1 2 Next >>