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

The thiazide-sensitive Na+:Cl- cotransporter is the major salt transport pathway in the distal convoluted tubule of the kidney, and a role of this cotransporter in blood pressure homeostasis has been defined by physiological studies on pressure natriuresis and by its involvement in monogenic diseases that feature arterial hypotension or hypertension. Data base analysis revealed that 135 single nucleotide polymorphisms along the human SLC12A3 gene that encodes the Na+:Cl- cotransporter have been reported. Eight are located within the coding region, and one results in a single amino acid change; the residue glycine at the position 264 is changed to alanine (G264A). This residue is located within the fourth transmembrane domain of the predicted structure. Because Gly-264 is a highly conserved residue, we studied the functional properties of this polymorphism by using in vitro mutagenesis and the heterologous expression system in Xenopus laevis oocytes. G264A resulted in a significant and reproducible reduction ( approximately 50%) in (22)Na+ uptake when compared with the wild type cotransporter. The affinity for extracellular Cl- and for thiazide diuretics was increased in G264A. Western blot analysis showed similar immunoreactive bands between the wild type and the G264A cotransporters, and confocal images of oocytes injected with enhanced green fluorescent protein-tagged wild type and G264A cotransporter showed no differences in the protein surface expression level. These observations suggest that the G264A polymorphism is associated with reduction in the substrate translocation rate of the cotransporter, due to a decrease in the intrinsic activity. Our study also reveals a role of the transmembrane segment 4 in defining the affinity for extracellular Cl- and thiazide diuretics.
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PMID:A single nucleotide polymorphism alters the activity of the renal Na+:Cl- cotransporter and reveals a role for transmembrane segment 4 in chloride and thiazide affinity. 1476 43

A family of orphan transporters has been discovered that are structurally related to the Na(+)-Cl(-)-dependent neurotransmitter transporters, including the dopamine transporter. One member of this family, the mouse XT2 gene, is predominantly expressed in the kidney and has 95% homology to rat ROSIT (renal osmotic stress-induced Na(+)-Cl(-) organic solute cotransporter). To study the physiological functions of this transporter, we generated XT2-knockout mice by gene targeting. XT2(-/-) mice develop and survive normally with no apparent abnormalities. To attempt to identify potential substrates for XT2, we screened urine from XT2-knockout mice by high-pressure liquid chromatography and mass spectrometry and found significantly elevated concentrations of glycine. To study glycine handling, XT2(+/+) and XT2(-/-) mice were injected with radiolabeled glycine, and urine samples were collected to monitor glycine excretion. After 2 h, XT2(-/-) mice were found to excrete almost twice as much glycine as the XT2(+/+) controls (P = 0.03). To determine whether the absence of the XT2 transporter affected sodium and fluid homeostasis, we measured systolic blood pressure by computerized tail-cuff manometry. Systolic blood pressure was significantly higher in XT2(-/-) mice (127 +/- 3 mmHg) than in wild-type controls (114 +/- 2 mmHg; P < 0.001). This difference in systolic blood pressure was maintained on high and low salt feeding. To examine whether the alteration in blood pressure and the defect in glycine handling were related, we measured systolic blood pressure in the XT2(-/-) mice during dietary glycine supplementation. Glycine loading caused systolic blood pressure to fall in the XT2(-/-) mice from 127 +/- 3 to 115 +/- 3 mmHg (P < 0.001), a level virtually identical to that of the wild-type controls. These data suggest that the XT2 orphan transporter is involved in glycine reabsorption and that the absence of this transporter is sufficient to cause hypertension.
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PMID:Hypertension and impaired glycine handling in mice lacking the orphan transporter XT2. 1512 38

Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.
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PMID:Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene. 1524 Jun 53

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on membrane potential and transmembrane ion gradients. In myocytes, neurons, and nephron cells, NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. Recently, the benzyloxyphenyl derivatives KB-R7943, SEA0400, and SN-6 have been developed as selective NCX inhibitors. Currently, SEA0400 is the most potent and selective inhibitor. These inhibitors possess different isoform-selectivities, although they have similar properties, such as Ca2+ influx mode-selectivity and I1 inactivation-dependence. Recent site-directed mutagenesis has revealed that these inhibitors possess some molecular determinants (Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839) for interaction with NCX1. These benzyloxyphenyl derivatives are expected to be useful tools to study the physiological roles of NCX. Moreover, such inhibitors may have therapeutic potential as a new remedy for ischemic disease, arrhythmias, heart failure, and hypertension.
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PMID:Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ exchange inhibitors. 1535 84

To evaluate the presence of hyperfiltration in two-kidney, one clip (2K, 1C) Goldblatt hypertensive rats, micropuncture studies of the unclipped kidney were used to examine renal functional reserve (RFR) with glycine (G) infusion in normal (N) rats and 2K, 1C rats. Systemic hypertension in 2K, 1C rats was associated with significantly increased values of single-nephron glomerular filtration rate (SNGFR), glomerular plasma flow (QA) and glomerular capillary hydrostatic pressure (PGC) when compared with N rats. Glycine infusion produced a marked increase in SNGFR, QA and whole-kidney GFR in N rats. In contrast, no changes were observed in these parameters in 2K, 1C rats. Lack of response in 2K, 1C rats was related to the failure of renal vessels to dilate during G infusion. These results suggest that loss of renal functional reserve in systemic hypertension is dependent on an abnormal function of renal vascular resistances.
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PMID:Evaluation of renal functional reserve of contralateral kidney of two-kidney, one clip Goldblatt hypertensive rats. 1536 35

We recently found in a white population that the genes encoding angiotensin-converting enzyme (ACE, I/D polymorphism), alpha-adducin (Gly460Trp), and aldosterone synthase (-344C/T) jointly influence renal function. We therefore investigated in a Chinese population the associations between the serum concentrations of creatinine and uric acid and these three genetic polymorphisms. We genotyped 471 ethnic Han Chinese subjects from 125 nuclear families recruited in northern China via random population sampling (75%) and at specialized hypertension clinics (25%). We performed population-based and family-based association analyses using generalized estimating equations (GEE) and quantitative transmission disequilibrium test (QTDT), respectively, while controlling for covariables. The participants were 39.7 years old and included 235 women (49.9%). The blood pressure measured at the subjects' homes averaged 126/80 mmHg. Mean values were 71 micromol/l for serum creatinine, 111 ml min(-1) 1.73 m(-2) for calculated creatinine clearance, and 236 micromol/l for serum uric acid. With adjustment for covariables, GEE analyses of single genes demonstrated that serum uric acid, but not serum creatinine, was positively associated with the ACE D allele. Serum uric acid concentrations were 15.8 micromol/l (95% confidence interval 3.3-28.2) and 25.7 micromol/l (11.1-40.2) higher in DD homozygotes than in ID and II subjects, respectively. Further GEE analyses of the three genes combined showed that the association between serum uric acid and the ACE polymorphism was confined to carriers of the alpha-adducin Gly and/or aldosterone synthase C alleles. Sensitivity analyses in parents and offspring separately as well as QTDT analyses were confirmatory. Among 114 informative offspring carrying the alpha-adducin Gly allele serum uric acid was significantly and positively associated with the transmission of the ACE D allele (beta=20.7 micromol/l). In conclusion, the present study extends our previous findings on the combined effects of the three candidate genes and supports the concept that these genetic polymorphisms jointly influence renal function.
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PMID:Renal function in relation to three candidate genes in a Chinese population. 1537 62

Previous studies have suggested that the Gly460Trp polymorphism of the alpha-adducin gene (ADD-1) is associated with salt sensitivity and primary hypertension. The results of linkage or association studies of ADD-1 of different populations are controversial. This study investigated the relationship between the Gly460Trp polymorphism of ADD-1 and essential hypertension in a Korean population. The subjects (n=903) were participants in a population-based study in Jangseong County, Korea. The Gly460Trp polymorphism of ADD-1 was determined using a polymerase chain reaction method. The frequency of the 460Trp allele was 59.4% in normotensives and 61.1% in hypertensives (p=0.523). The frequencies of the genotypes did not differ significantly between the hypertensive and normotensive groups (16.3% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in normotensives; 16.2% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in hypertensives; p=0.928). After adjusting for other risk factors, Gly/Trp and Trp/Trp were not associated with hypertension (OR 1.00, 95% CI 0.65-1.53, Gly/Trp vs. Gly/Gly; OR 1.22, 95% CI 0.79-1.90, Trp/Trp vs. Gly/Gly). These findings suggest that the Gly460Trp polymorphism of ADD-1 is not associated with hypertension.
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PMID:Alpha-adducin Gly460Trp polymorphism and essential hypertension in Korea. 1560 90

The aim of this study was to investigate the association between polymorphisms in the beta(2)-adrenergic receptor gene (ADRB2) (-47C/T, Arg16/Gly, Gln27/Glu) and stage-2 hypertension in northern Han Chinese. We recruited 503 individuals with stage-2 hypertension and 504 age-, gender-, and area-matched controls from the International Collaborative Study of Cardiovascular Disease in Asia. Genotyping was performed using PCR-RFLP. Logistic regression analyses revealed that carriers of the Gly16 allele had a significantly higher odds ratio (OR) for hypertension, while carriers of the Glu27 allele had a significantly lower OR. In multivariate linear regression analyses, the Arg16/Gly and Gln27/Glu genotypes were significantly associated with systolic blood pressure level (p = 0.004 and p < 0.001, respectively). In haplotype analyses, we found the frequency of haplotypes composed of the Gly16 and Gln27 alleles was significantly higher, whereas the frequency of haplotypes composed of the Arg16 and Glu27 alleles was significantly lower, in hypertensives compared to their controls (both p = 0.001). These results indicate that the Gly16 and Gln27 alleles of the ADRB2 gene confer an increased risk for stage-2 hypertension in this northern Han Chinese population.
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PMID:beta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese. 1563 26

PGC-1alpha is a coactivator of numerous transcription factors and is expressed in tissues with high energy demands and abundant in mitochondria. It is induced in the myocardium on fasting and physical exercise, and cardiac-specific overexpression stimulates mitochondrial biogenesis in mice. The common Gly482Ser polymorphism of PGC-1alpha has previously shown association with arterial hypertension among Austrian men. Thus, we aimed at investigating this relationship in the Danish white population. The Gly482Ser polymorphism was genotyped in a total of 2562 Danish white subjects using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and a GenoView locked nucleic acid assay (LNA), and the relationships of this variant with blood pressure levels and arterial hypertension were analyzed. Furthermore, we performed a combined analysis of the data from the present study in combination with previously published results. The Ser/Ser genotype was significantly associated with a reduced risk of hypertension and with lower systolic, diastolic, and mean arterial blood pressure levels, predominantly among women. Finally, in a combined analysis using data obtained in both sexes, the Ser/Ser genotype group had an estimated odds ratio of 0.70 (95% confidence interval, 0.56 to 0.86) for hypertension compared with Gly/X carriers (P=0.001). In conclusion, the Ser allele of PGC-1alpha Gly482Ser confers a significantly reduced risk of hypertension in whites. Further studies are needed to elucidate the differential role of this polymorphism in men and women.
Hypertension 2005 Apr
PMID:PGC-1alpha Gly482Ser polymorphism associates with hypertension among Danish whites. 1573 46

Renal control of Na(+) regulation is a critical component to blood pressure regulation. It has recently been suggested that the beta-2 adrenergic receptor plays a role in blood pressure regulation possibly via renal epithelial sodium channels (ENaC). In the kidneys, gain of function mutations of the ENaC leads to increased salt-sensitivity and hypertension (Liddle's syndrome). In contrast, loss of function mutations of the ENaC leads to pseudohypoaldosteronism and is characterized by hypotension. Polymorphic variation of the beta-2 adrenergic receptor (beta2AR, the Arg16Gly polymorphism) leads to differences in physiologic function, in vivo. Specifically, subjects homozygous for Glycine at amino acid 16 have been shown to have enhanced forearm blood flow in response to isoproterenol and better airway function at baseline and during exercise when compared to subjects homozygous for Arginine at amino acid 16. We hypothesize, therefore, that subjects that are homozygous for Gly at amino acid 16 of the beta2AR have higher baseline blood pressure than Arg16 homozygotes due to beta2AR-mediated increases in ENaC activity in the kidney, caused, at least in part, by greater beta2AR density or enhanced beta2AR function of the Gly16 group.
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PMID:Blood pressure variation in healthy humans: a possible interaction with beta-2 adrenergic receptor genotype and renal epithelial sodium channels. 1592 2


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