UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone proteins are essential components of eukaryotic chromosomes. In metazoans, they are produced from the so-called replication-dependent histone genes. The biogenesis of histones is tightly coupled to DNA replication in a stoichiometric manner because an excess of histones is highly toxic for the cell. Therefore, a strict cell cycle-regulation of critical factors required for histone expression ensures exclusive S-phase expression. This review focuses on the molecular mechanisms responsible for such a fine expression regulation. Among these, a large part will be dedicated to post-transcriptional events occurring on histone mRNA, like histone mRNA 3' end processing, nucleo-cytoplasmic mRNA export, translation and mRNA degradation. Many factors are involved, including an RNA-binding protein called HBP, also called SLBP (for hairpin- or stem-loop-binding protein) that binds to a conserved hairpin located in the 3' UTR part of histone mRNA. HBP plays a pivotal role in the expression of histone genes since it is necessary for most of the steps of histone mRNA metabolism in the cell. Moreover, the strict S-phase expression pattern of histones is achieved through a fine cell cycle-regulation of HBP. A large part of the discussion will be centered on the critical role of HBP in histone biogenesis.
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PMID:Expression of metazoan replication-dependent histone genes. 1616 92

The renin-angiotensin system (RAS) regulates BP and may affect chronic kidney disease (CKD) through induction of tissue growth and fibrosis. The angiotensinogen (AGT) promoter G(-6) allele lowers transcription and is inversely associated with hypertension. In white individuals, the A1166C 3'-UTR variant of angiotensin II type 1 receptor (AT1R) has been associated with CKD. CKD associations with these RAS genes are uncertain in high-risk black populations. A prospective population-based study of CKD risk was conducted among 3706 black individuals without severe renal dysfunction at baseline (serum creatinine > or =177 micromol/L [2.0 mg/dl] for men, > or =159 micromol/L [1.8 mg/dl] for women) to examine associations with AGT and AT1R. Incident CKD progression was defined as kidney disease hospitalization or increase in serum creatinine level > or =35 micromol/L (0.4 mg/dl) above baseline. During mean follow-up of 10.2 yr, CKD progression incidence rate (per 1000 person-years) was 8.2 (n = 312 cases). Risk was lower for AGT G(-6) carriers compared with A(-6) (incidence 6.9 versus 9.0; log-rank P = 0.03) and nonsignificantly higher among AT1R C1166 carriers. Adjusting for hypertension and major CKD risk factors, AGT G(-6)decreased risk (relative risk 0.75; 95% confidence interval 0.57 to 0.98). AT1R C1166 increased risk only among those with hypertension (relative risk 1.65; 95% confidence interval 1.14 to 2.39). The AGT G(-6)A polymorphism may play a role in CKD progression in black individuals, consistent with in vitro effects on AGT levels and renal remodeling but independent of BP. The AT1R C1166 allele may increase susceptibility but only in the presence of hypertension.
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PMID:Genetic variation of the renin-angiotensin system and chronic kidney disease progression in black individuals in the atherosclerosis risk in communities study. 1639 64

Sexual dimorphism in blood pressure (BP) regulation has been observed both in humans and experimental animals, and estrogens have been shown to contribute to this epidemiological observation. A key enzyme in determining estrogen levels is aromatase cytochrome P450. The aim of this study was to evaluate the role of the gene encoding aromatase, CYP19A1, as an independent risk factor for hypertension and its relationship with systolic and diastolic BP measures. We genotyped 2 polymorphisms within the CYP19A1 gene, IVS4 rs11575899 and 3'UTR rs10046, in 3448 individuals. In quantitative analysis, we observed significant associations between the 2 polymorphisms and BP values in women, being these associations dependent on BMI and independent of menopause status. The case-control analysis revealed that the most prominent associations were found for nonobese women in diastolic hypertension (DHT): the IVS4_22 and 3'UTR_11 are risk genotypes (OR=1.61, P=0.027 and OR=1.59, P=0.012, respectively), whereas IVS4_11 and 3'UTR_22 genotypes have a protective effect against DHT (OR=0.63, P=0.009, and OR=0.61, P=0.020, respectively). Haplotype analysis confirmed the above associations: among nonobese women the haplotype 21 is overrepresented in hypertensive women (OR=1.33, P=0.004, for DHT and OR=1.25, P=0.026, for systolic hypertension, SHT) and, conversely, the haplotype 12 protects against hypertension (OR=0.78, P=0.015 for DHT and OR=0.82, P=0.04 for SHT). Our study has shown that the CYP19A1 gene may be involved in the genetic regulation of BP in women. This effect is dependent on BMI and independent of menopause status, suggesting that this action is mainly driven by aromatase activity in fat tissue.
Hypertension 2007 Nov
PMID:Sex and body mass index specific regulation of blood pressure by CYP19A1 gene variants. 1789 73

Cystic kidney disease has been linked to mutations in the Invs gene in mice with an inversion of embryonic turning (inv/inv) and the INVS (NPHP2) gene in human infantile nephronophthisis (NPH). Infantile NPH shows marked cyst formation in contrast to other forms of NPH and rapidly progresses to end-stage renal failure (ESRD) before 5 years of age. In this report, we describe an adolescent with a mutation in INVS who had preservation of his renal function beyond infancy. The patient showed findings of NPH with mild renal insufficiency together with situs inversus. He also exhibited a series of features consistent with Jeune syndrome involving asphyxiating thoracic dystrophy, heart failure and hypertension prior to advanced renal insufficiency. Based upon these features, our patient is likely to have the combined clinical features of infantile NPH with Jeune syndrome. Genetic analysis for INVS disclosed a heterozygous mutation of TrG at position rs7024375 in the 5'UTR of INVS in the patient and his mother, while no abnormalities were found in any of the 17 exons of INVS or NPHP1, 3 and 4. To our knowledge, this is the first patient possessing a genetic alteration in INVS who had preservation of renal function past childhood. This study suggests that our patient may be a compound heterozygote for infantile NPH and Jeune syndrome, because both these disorders are transmitted mainly as an autosomal-recessive trait.
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PMID:Association of INVS (NPHP2) mutation in an adolescent exhibiting nephronophthisis (NPH) and complete situs inversus. 1821 8

Chromogranin A is released together with epinephrine and norepinephrine from catecholaminergic cells. Specific endopeptidases cleave chromogranin A into biologically active peptide fragments, including catestatin, which inhibits catecholamine release. Previous studies have suggested that a deficit in this sympathetic "braking" system might be an early event in the pathogenesis of human hypertension. Whether chromogranin A (CHGA) polymorphisms predict end-organ complications of hypertension, such as end-stage renal disease, is unknown. Among blacks, we studied common genetic variants spanning the CHGA locus in 2 independent case-control studies of hypertensive ESRD. Two haplotypes were significantly more frequent among subjects with hypertensive ESRD: 1) in the promoter (5') region, G-462A-->T-415C-->C-89A, haplotype ATC (adjusted odds ratio = 2.65; P = 0.037), and 2) at the 3'-end, C11825T (3'-UTR, C+87T)-->G12602C, haplotype TC (adjusted odds ratio = 2.73, P = 0.0196). Circulating levels of catestatin were lower among those with hypertensive ESRD than controls, an unexpected finding given that peptide levels are usually elevated in ESRD because of reduced renal elimination. We found that the 3'-UTR + 87T variant decreased reporter gene expression, providing a possible mechanistic explanation for diminished catestatin. In summary, common variants in chromogranin A associate with the risk of hypertensive ESRD in blacks.
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PMID:Chromogranin A polymorphisms are associated with hypertensive renal disease. 1827 38

Regulation of angiotensin II type 1 receptor (AT1R) has a pathophysiological role in hypertension, atherosclerosis and heart failure. We started from an observation that the 3'-untranslated region (3'-UTR) of AT1R mRNA suppressed AT1R translation. Using affinity purification for the separation of 3'-UTR-binding proteins and mass spectrometry for their identification, we describe glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an AT1R 3'-UTR-binding protein. RNA electrophoretic mobility shift analysis with purified GAPDH further demonstrated a direct interaction with the 3'-UTR while GAPDH immunoprecipitation confirmed this interaction with endogenous AT1R mRNA. GAPDH-binding site was mapped to 1-100 of 3'-UTR. GAPDH-bound target mRNAs were identified by expression array hybridization. Analysis of secondary structures shared among GAPDH targets led to the identification of a RNA motif rich in adenines and uracils. Silencing of GAPDH increased the expression of both endogenous and transfected AT1R. Similarly, a decrease in GAPDH expression by H(2)O(2) led to an increased level of AT1R expression. Consistent with GAPDH having a central role in H(2)O(2)-mediated AT1R regulation, both the deletion of GAPDH-binding site and GAPDH overexpression attenuated the effect of H(2)O(2) on AT1R mRNA. Taken together, GAPDH is a translational suppressor of AT1R and mediates the effect of H(2)O(2) on AT1R mRNA.
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PMID:Posttranscriptional regulation of angiotensin II type 1 receptor expression by glyceraldehyde 3-phosphate dehydrogenase. 1924 43

Inflammation plays a crucial role in the pathogenesis of type 2 diabetes and various lines of evidences suggest an important contribution of type 2 receptor for TNFalpha (TNFR2), a mediator of inflammatory responses. Though genetic association of TNFRSF1B (encoding TNFR2) polymorphisms have been investigated in various studies, their involvement is not clear because of inconsistent findings. Because of high susceptibility of Indian population to type 2 diabetes and its complications, we evaluated the association of TNFRSF1B polymorphisms-rs1061622 (M196R; exon6) and rs3397 (3'UTR) and (CA)( n ) repeat (intron 4) in 1,852 subjects including 1,040 cases and 812 controls with type 2 diabetes and its associated peripheral neuropathy and hypertension in North Indians of Indo-European ethnicity. The allelic and genotypic distributions of these polymorphisms were comparable among healthy control vs. type 2 diabetes, peripheral neuropathy vs. non-neuropathy and hypertensive vs. normotensive groups. (CA)( n ) polymorphism has been shown to be associated with diabetic neuropathy in Caucasians, however, this could not be replicated in our study (P = 0.27). None of the polymorphisms were found to influence the 14 anthropometric and biochemical traits related to type 2 diabetes studied here. Thus, we conclude that TNFRSF1B is not a major contributing factor to the genetic risk of type 2 diabetes, its associated peripheral neuropathy and hypertension and related metabolic traits in North Indians.
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PMID:Association analysis of TNFRSF1B polymorphisms with type 2 diabetes and its related traits in North India. 1934 43

Metabolic syndrome, a clustering of conditions including obesity, insulin resistance, and hypertension, is a risk factor for cardiovascular morbidity and mortality. Because peroxisome proliferator-activated receptor gamma (PPARgamma) regulates adipocyte differentiation and lipid metabolism and is the molecular target of a class of insulin sensitizers, genetic variants that alter Pparg gene expression are potential contributors to the metabolic syndrome. To test this possibility, we generated mice having 182% of the normal steady-state level of PPARgamma mRNA by replacing the 3'-UTR of the natural Pparg gene with that of the beta-globin gene, thereby stabilizing the Pparg transcripts. This increase in PPARgamma mRNA level had no apparent consequences in various physiological parameters, except that the mice repeatedly showed a trend toward lower blood pressures (by about 3 mm Hg) than their WT littermates. In contrast, the opposite trend, toward increased blood pressure, was observed in mice with genetically reduced levels of PPARgamma mRNA as a consequence of insertion of an allele with an mRNA-destabilizing sequence into the endogenous 3'-UTR of the Pparg gene. By combining 12 sets of blood pressure measurements in more than 350 mutant mice having PPARgamma expression levels varying from 28% to 182% and more than 280 WT littermates, we show that a 2-fold genetic increase (or decrease) in PPARgamma expression levels decreases (or increases) blood pressure by about 2.8 mm Hg. Thus, our experiments demonstrate that quantitative variants causing decreased Pparg expression are a potential causative risk factor for essential hypertension.
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PMID:Genetic variations in peroxisome proliferator-activated receptor gamma expression affect blood pressure. 1988 95

MicroRNAs (miRNAs) comprise a post-transcriptional layer of gene regulation shown to be involved in diverse physiological processes. We aimed to study whether regulatory networks that determine susceptibility to hypertension may involve a miRNA component. Screening of loci, involved in renal water-salt balance regulation, highlighted the mineralocorticoid receptor gene NR3C2 as a potential target for several miRNAs. A luciferase assay demonstrated that miR-124 and miR-135a suppress NR3C2 3'UTR reporter construct activity 1.5- and 2.2-fold, respectively. As the tested miRNAs did not reduce the levels of target mRNA, we suggest that the binding of miR-124 and miR-135a to NR3C2 3'UTR contributes to the translational, not transcriptional regulation of the gene. Co-expression of two different miRNAs did not increase the repression of the reporter gene, indicating no additive or synergistic effects between the tested miRNAs. Our results demonstrate that by repressing the mineralocorticoid receptor gene NR3C2, miR-124 and miR-135a could participate in the regulation of renin-angiotensin-aldosterone system and thereby might be involved in blood pressure regulation.
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PMID:MicroRNAs miR-124 and miR-135a are potential regulators of the mineralocorticoid receptor gene (NR3C2) expression. 1994 75

Human with-no-lysine kinase-4 (hWNK4) is a member of the serine-threonine protein kinase family and may be involved in pathophysiological processes of hypertension through regulating diverse ion transporters. We are interested in the molecular mechanism of regulating hWNK4 expression. The 3'-untranslated region (3'-UTR) is an important area for gene regulation. Here, we focused on the 3'-UTR of hWNK4 to investigate how it regulates hWNK4 expression. A luciferase assay showed that the hWNK4 3'-UTR obviously enhanced the transcriptional activity of the promoter, whether homologous or heterologous. Chromosome conformation capture assay further demonstrated that the 3'-UTR enhancer functioned through distant crosstalking with the hWNK4 promoter in a cell-specific manner. Following the deletion of the promoter, the enhancer action of the hWNK4 3'-UTR fell away, indicating that the motifs within the promoter could be essential for the function of the hWNK4 3'-UTR. The hWNK4 3'-UTR, meanwhile, contained a miR-296 binding site, predicted by bioinformatics algorithms and verified as a true target using a reporter assay. Expression of hWNK4 can be downregulated by miR-296 at the posttranscriptional level in cell-specific pattern, shown by real-time quantitative PCR and Western blot assays. These data demonstrate the hWNK4 3'-UTR plays an enhancer role by crosstalking with the promoter, and miR-296 suppresses hWNK4 expression through targeting on its 3'-UTR in a cell-specific fashion. The coordinated modulation of miR-296 and cofactors on the 3'-UTR may be attributed to hWNK4 physiopathological function.
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PMID:Human with-no-lysine kinase-4 3'-UTR acting as the enhancer and being targeted by miR-296. 2056 97

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