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

The relative importance of molecular biology in clinical practice is often underestimated. However, numerous procedures in clinical diagnosis and new therapeutic drugs have resulted from basic molecular research. Furthermore, understanding of the physiological and physiopathological mechanisms underlying several human diseases has been improved by the results of basic molecular research. For example, cloning of the gene encoding leptin has provided spectacular insights into the understanding of the mechanisms involved in the control of food intake and body weight maintenance in man. In cystic fibrosis, the cloning and identification of several mutations in the gene encoding the chloride channel transmembrane regulator (CFTR) have resolved several important issues in clinical practice: cystic fibrosis constitutes a molecular defect of a single gene. There is a strong correlation between the clinical manifestations or the severity of the disease (phenotype) with the type of mutations present in the CFTR gene (genotype). More recently, identification of mutations in the gene encoding a subunit of the renal sodium channel in the Liddle syndrome has provided important insight into the physiopathological understanding of mechanisms involved in this form of hereditary hypertension. Salt retention and secondary high blood pressure are the result of constitutive activation of the renal sodium channel by mutations in the gene encoding the renal sodium channel. It is speculated that less severe mutations in this channel could result in a less severe form of hypertension which may correspond to patients suffering from high blood pressure with low plasma renin activity. Several tools, most notably PCR, are derived from molecular research and are used in everyday practice, i.e. in prenatal diagnosis and in the diagnosis of several infectious diseases including tuberculosis and hepatitis. Finally, the production of recombinant proteins at lower cost and with fewer side effects is used in everyday clinical practice. Gene therapy remains an extraordinary challenge in correcting severe hereditary or acquired diseases. The use of genetically modified animal cell lines producing growth factors, insulin or erythropoetin, which are subsequently encapsulated and transferred to man, represents an attractive approach for gene therapy.
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PMID:[Is molecular biology useful to the practitioner?]. 919 Jun 68

We report that a genetic polymorphism of the alpha2-adrenergic receptor (A2AR) encoded by chromosome 10 is associated with hypertension and an increase in epinephrine-mediated platelet aggregation in humans. The mechanism responsible for this heritable contrast in sensitivity to epinephrine is unknown. We tested our hypothesis that epinephrine-induced platelet aggregation is mediated by activation of chloride transport. We measured epinephrine-mediated increases in optical density of gel-filtered platelets suspended in a bicarbonate-buffered physiological salt solution. Compared with platelets incubated in the control buffer (130 mmol/L NaCl), platelets incubated with either bumetanide, a Na/K/2Cl cotransport inhibitor; anthracene-9-carboxylic acid, a chloride channel blocker; or acetazolamide, an agent that blocks ATP-dependent chloride transport had significantly decreased aggregation responses to epinephrine. When measured fluorometrically, epinephrine significantly increased intraplatelet chloride concentrations. Chloride-dependent modifications of epinephrine-induced platelet aggregation were not attributable to changes in A2AR ligand binding characteristics or to the concentration of platelet cAMP. Finally, subthreshold concentrations of epinephrine also potentiated thrombin-induced platelet aggregation, and blockade of chloride transport diminished this synergistic action of epinephrine on thrombin-stimulated platelet aggregation. Heritable differences in epinephrine-mediated platelet aggregation may be attributable to genetic differences in chloride transport in platelets. Furthermore, because we observed a necessary role for chloride transport in epinephrine-mediated platelet aggregation, pharmacological agents that block chloride transport, such as diuretics, may provide salutary protection against vascular thrombosis in patients with hypertension independent of the effect of these drugs on blood pressure.
Hypertension 1998 Feb
PMID:Mechanism of epinephrine-induced platelet aggregation. 946 Dec 28

Advances in the molecular genetics of inherited renal tubulopathies have allowed some insight into the normal mechanisms of tubular cation and anion reabsorption. It is now possible to view Bartter's syndrome, Gitelman's syndrome and pseudohypoaldosteronism type 1 as having genetic abnormalities which produce tubular defects that are similar to those induced by the pharmacological actions of loop diuretics, thiazide diuretics or potassium-sparing diuretics, respectively. Although these rare monogenic disorders with dramatic phenotypes seem to have little relevance to everyday clinical practice, it is possible that subtle abnormalities of the regulation of the ENaCs may play a role in low-renin forms of 'essential' hypertension. Similarly, subtle abnormalities in the function of the electroneutral sodium-(potassium)-chloride cotransporters (NKCC2 and NCCT) and the renal CLC-type chloride channels (CLC5) may be major determinants of urinary calcium excretion with roles in the pathogenesis of 'idiopathic' hypercalciuria and osteoporosis. Because of the intricate and diverse molecular mechanisms by which tubular reabsorption of water and solutes takes place in each different nephron segment, it is likely that other renal channels and transporters will be implicated in the pathogenesis of further monogenic disorders, and that these will allow additional insights into tubular functioning. Recent studies have demonstrated that in addition to abnormalities in the NKCC2 and ROMK1 genes, mutations at a third genetic locus can also cause Bartter's syndrome. Linkage studies, followed by mutational analyses have found deletions and point mutations in the gene encoding one of the TAL-specific chloride channels, CLCKB, in 17 Bartter's families. This chloride channel is similar in structure to CLC5, and is located on the long arm of chromosome 1. Importantly, there appears to be a phenotypic difference between subjects with Bartter's syndrome due to CLCKB abnormalities and those with NKCC2 or ROMK1 mutations. Despite the fact that all of these Bartter's patients had significant hypercalciuria, nephrocalcinosis was not found in any of the 17 subjects with CLCKB mutations, compared to 19 of 20 patients with NKCC2 or ROMK1 mutations. These findings have also demonstrated a key role for CLCKB as a major basolateral chloride channel involved in mTAL sodium and chloride reabsorption (Figure 2).
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PMID:Straightening out the renal tubule: advances in the molecular basis of the inherited tubulopathies. 951 7

Interest in the functions of intracellular chloride expanded about twenty years ago but mostly this referred to tissues other than smooth muscle. On the other hand, accumulation of chloride above equilibrium seems to have been recognised more readily in smooth muscle. Experimental data is used to show by calculation that the Donnan equilibrium cannot account for the chloride distribution in smooth muscle but it can in skeletal muscle. The evidence that chloride is normally above equilibrium in smooth muscle is discussed and comparisons are made with skeletal and cardiac muscle. The accent is on vascular smooth muscle and the mechanisms of accumulation and dissipation. The three mechanisms by which chloride can be accumulated are described with some emphasis on calculating the driving forces, where this is possible. The mechanisms are chloride/bicarbonate exchange, (Na+K+Cl) cotransport and a novel entity, "pump III", known only from own work. Their contributions to chloride accumulation vary and appear to be characteristic of individual smooth muscles. Thus, (Na+K+Cl) always drives chloride inwards, chloride/bicarbonate exchange is always present but does not always do it and "pump III" is not universal. Three quite different biophysical approaches to assessing chloride permeability are considered and the calculations underlying them are worked out fully. Comparisons with other tissues are made to illustrate that low chloride permeability is a feature of smooth muscle. Some of the functions of the high intracellular chloride concentrations are considered. This includes calculations to illustrate its depolarising influence on the membrane potential, a concept which, experience tells us, some people find confusing. The major topic is the role of chloride in the regulation of smooth muscle contractility. Whilst there is strong evidence that the opening of the calcium-dependent chloride channel leads to depolarisation, calcium entry and contraction in some smooth muscles, it appears that chloride serves a different function in others. Thus, although activation and inhibition of (Na+K+Cl) cotransport is associated with contraction and relaxation respectively, the converse association of inhibition and contraction has been seen. Nevertheless, inhibition of chloride/bicarbonate exchange and "pump III" and stimulation of (K+Cl) cotransport can all cause relaxation and this suggests that chloride is always involved in the contraction of smooth muscle. The evidence that (Na+K+Cl) cotransport more active in experimental hypertension is discussed. This is a common but not universal observation. The information comes almost exclusively from work on cultured cells, usually from rat aorta. Nevertheless, work on smooth muscle freshly isolated from hypertensive rats confirms that (Na+K+Cl) cotransport is activated in hypertension but there are several other differences, of which the depolarisation of the membrane potential may be the most important.Finally, a simple calculation is made which indicates as much as 40% of the energy put into the smooth muscle cell membrane by the sodium pump is necessary to drive (Na+K+Cl) cotransport. Notwithstanding the approximations in this calculation, this suggests that chloride accumulation is energetically expensive. Presumably, this is related to the apparently universal role of chloride in contraction.
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PMID:Chloride in smooth muscle. 1122 12

Ubiquitylation has emerged as an important mechanism for controlling surface expression of membrane proteins. This post-translational modification involves the sequential action of several enzymes including a ubiquitin-activating enzyme E1, a ubiquitin-conjugating enzyme E2 and a ubiquitin-protein ligase E3. E3s are responsible for substrate recognition. Here we describe the role of the Nedd4/Nedd4-like family of ubiquitin-protein ligases in the regulation of proteins involved in epithelial transport. The Nedd4/Nedd4-like proteins are composed of a N-terminal C2 domain, several WW domains and a catalytic HECT domain. The epithelial Na(+) channel ENaC is the best studied example of a Nedd4/Nedd4-like substrate. Its cell surface expression is regulated by the ubiquitin-protein ligase Nedd4-2 via direct PY motif/WW domain interaction. This regulatory mechanism is impaired in Liddle's disease, an inherited form of human hypertension, and is controlled by Sgk1, an aldosterone-inducible kinase which phosphorylates Nedd4-2. The regulation of ENaC by Nedd4-2 is a paradigm for the control of epithelial membrane proteins, as evidenced by the regulation of the ClC-5 chloride channel by the ubiquitin-protein ligase WWP2 or the tight junction protein Occludin by Itch.
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PMID:The role of Nedd4/Nedd4-like dependant ubiquitylation in epithelial transport processes. 1269 68

The chloride channel ClC-Kb is expressed in the basolateral cell membrane of the distal nephron and participates in renal NaCl reabsorption. Loss-of-function mutations of ClC-Kb lead to classic Bartter syndrome, a rare salt-wasting disorder. Recently, we identified the ClC-Kb(T481S) polymorphism, which confers a strong gain-of-function effect on the ClC-Kb chloride channel. The present study has been performed to explore the prevalence of the mutation and its functional significance in renal salt handling and blood pressure regulation. As evident from electrophysiological analysis with the 2-electrode voltage-clamp technique, heterologous expression of ClC-Kb(T481S) in Xenopus oocytes gave rise to a current that was 7-fold larger than the current produced by wild-type ClC-Kb. The prevalence of the mutant allele was significantly higher in an African population from Ghana (22%) than in whites (12%). As tested in 1 white population, carriers of ClC-Kb(T481S) were associated with significantly higher systolic (by approximately 6.0 mm Hg) and diastolic (by approximately 4.2 mm Hg) blood pressures and significantly higher prevalence (45% versus 25%) of hypertensive (> or =140/90 mm Hg) blood pressure levels. Individuals carrying ClC-Kb(T481S) had significantly higher plasma Na+ concentrations and significantly decreased glomerular filtration rate. In conclusion, the mutation ClC-Kb(T481S) of the renal epithelial Cl- channel ClC-Kb strongly activates ClC-Kb chloride channel function in vitro and may predispose to the development of essential hypertension in vivo.
Hypertension 2004 Jun
PMID:Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. 1644 91

We report here the results of the GENIHUSS study (GENetic Investigation of Hypertension Undertaken in Sydney Sibships)-a genome-wide scan to identify loci linked to essential hypertension (HT). Subjects were Anglo-Celtic Australian sibpairs resident in or near Sydney, Australia, with onset of HT before age 60 years (mean, 44 +/- 13 SD years). A 10-cM scan involving 400 microsatellite markers and 252 HT sibpairs was followed by fine mapping of the most promising locus using 296 HT sibpairs (481 individuals from 200 families). Multipoint and two-point nonparametric linkage analyses were performed using MAPMAKER/SIBS, GENEHUNTER II, and SPLINK. Suggestive loci were found on chromosomes 1 (4 cM) and 4 (129 cM). The chromosome 4 locus coincided with a QTL for systolic blood pressure (BP) in the Australian Victorian Family Heart Study, and the locus on chromosome 1 contains the chloride channel gene CLCNKB and tumor necrosis factor receptor 2 gene TNFRSF1B, which have each shown association with HT. Our study adds to findings of HT loci emanating from genome scans.
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PMID:Genome-wide scan for hypertension in Sydney Sibships: the GENIHUSS study. 1592 43

Single nucleotide polymorphisms (SNPs) in genes encoding or influencing renal sodium transport systems were investigated as potential predictors of blood pressure (BP) response to a thiazide diuretic. A sample of 585 adults with essential hypertension (30 to 59.9 years of age; 50% blacks; 47% women) were treated with hydrochlorothiazide for 4 weeks (25 mg daily, orally) to determine office BP responses. Ambulatory BP responses were measured in a subset of 228 subjects. After adjustment for ethnicity, sex, age, and waist-to-hip ratio, 3 SNPs in WNK1 (rs2107614, rs2277869, and rs1159744), encoding a lysine-deficient protein kinase that regulates thiazide-sensitive sodium-potassium cotransport, made statistically significant contributions to predicting ambulatory BP responses, accounting for 2% to 4% of variation in systolic and diastolic responses (P<0.05). SNPs in the beta2-adrenoceptor (rs2400707) and the epithelial sodium channel gamma-subunit (rs5723 and rs5729) were associated with similar magnitude of variation in ambulatory systolic BP response (P=0.028) or office diastolic BP response (P<0.05), respectively. However, SNPs evaluated in the furosemide-sensitive sodium-potassium chloride cotransporter, potassium inwardly rectifying channel, chloride channel, thiazide-sensitive sodium chloride cotransporter, epithelial sodium channel beta-subunit, and the mineralocorticoid receptor were not associated with significant variation in ambulatory or office BP responses. Polymorphisms in genes regulating renal sodium transport, in particular WNK1, predict interindividual differences in antihypertensive responses to hydrochlorothiazide.
Hypertension 2005 Oct
PMID:WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. 1617 12

The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC. Treatment with 5-HT for 16h increased migration of PASMC up to four-fold as monitored in a modified Boyden chamber assay. Increased migratory responses were associated with cellular morphological changes and reorganization of the actin cytoskeleton. 5-HT-induced alterations in morphology were previously shown in our laboratory to require cAMP [Lee SL, Fanburg BL. Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. J Cell Phys 1992;150(2):396-405], and the 5-HT4 receptor was pharmacologically determined to be the primary activator of cAMP in bovine PASMC [Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-Hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol 1992;42(5):817-25]. We examined the role of the 5-HT4 receptor and cAMP in 5-HT-induced bovine PASMC migration. PASMC express 5-HT4 receptor mRNA, and a 5-HT4 receptor antagonist and a cAMP antagonist completely blocked 5-HT-induced cellular migration. Consistent with our previous report that a cAMP-dependent Cl(-) channel is required for 5-HT-induced morphological changes in PASMC, phenylanthranilic acid, a Cl(-) channel blocker, inhibited actin cytoskeletal reorganization and migration produced by 5-HT. We conclude that 5-HT stimulates PASMC migration and associated cytoskeletal reorganization through the 5-HT4 receptor and cAMP activation of a chloride channel.
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PMID:Serotonin induces pulmonary artery smooth muscle cell migration. 1631 35

The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-gated chloride channel. WNK kinases are widely expressed modulators of ion transport. WNK1 and WNK4, two WNK kinases that are mutated in familial hyperkalemic hypertension (FHHt), are co-expressed with CFTR in several organs, raising the possibility that WNK kinases might alter CFTR activity in vivo or that CFTR could be involved in the pathogenesis of FHHt. Here, we report that WNK1 co-localizes with CFTR protein in pulmonary epithelial cells. Co-expression of WNK1 or WNK4 with CFTR in Xenopus laevis oocytes suppresses chloride channel activity. The effect of WNK4 is dose dependent and occurs, at least in part, by reducing CFTR protein abundance at the plasma membrane. This effect is independent of WNK4 kinase activity. In contrast, the effect of WNK1 on CFTR activity requires intact WNK1 kinase activity. Moreover WNK1 and WNK4 exhibit additive CFTR inhibition. Previous reports suggest that patients with FHHt exhibit mild changes in nasal potential difference that resemble the more severe changes that occur in cystic fibrosis. We report that the FHHt-causing mutant WNK4 Q562E is a more potent inhibitor of CFTR activity than is the wild-type WNK4. Taken together, these results suggest that WNK1 and WNK4 may modulate CFTR activity; they further suggest that WNK kinases may be potential therapeutic targets for cystic fibrosis.
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PMID:WNK1 and WNK4 modulate CFTR activity. 1719 47


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