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 T594M polymorphism of the epithelial sodium channel is found in approximately 5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle's syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89+/-3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91+/-4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8+/-4/2 mm Hg (systolic, P<0.05; diastolic, P<0.01). On restarting amiloride, blood pressure was again controlled to 140/88+/-6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.
Hypertension 2002 Jul
PMID:Amiloride, a specific drug for hypertension in black people with T594M variant? 1210 31

The epithelial Na(+) channel (ENaC), located in the apical membrane of renal aldosterone-responsive epithelia, plays an essential role in controlling the Na(+) balance of extracellular fluids and hence blood pressure. As of now, ENaC is the only Na(+) transport protein for which genetic evidence exists for its involvement in the genesis of both hypertension (Liddle's syndrome) and hypotension (pseudohypoaldosteronism type 1). The regulation of ENaC involves a variety of hormonal signals (aldosterone, vasopressin, insulin), but the molecular mechanisms behind this regulation are mostly unknown. Two regulatory proteins have gained interest in recent years: the ubiquitin-protein ligase neural precursor cell-expressed, developmentally downregulated gene 4 isoform Nedd4-2, which negatively controls ENaC cell surface expression, and serum glucocorticoid-inducible kinase 1 (Sgk1), which is an aldosterone- and insulin-dependent, positive regulator of ENaC density at the plasma membrane. Here, we summarize present ideas about Sgk1 and Nedd4-2 and the lines of experimental evidence, suggesting that they act sequentially in the regulatory pathways governed by aldosterone and insulin and regulate ENaC number at the plasma membrane.
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PMID:Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport. 1216 87

The epithelial Na(+) channel (ENaC) is a critical component of the pathway maintaining salt and water balance. The channel is regulated by members of the Nedd4 family of ubiquitin-protein ligases, which bind to channel subunits and catalyze channel internalization and degradation. ENaC mutations that abolish this interaction cause Liddle's syndrome, a genetic form of hypertension. Here, we test the hypothesis that WW domain-containing protein 2 (WWP2), a member of the Nedd4 family of ubiquitin-protein ligases, is a candidate to regulate ENaC. Consistent with this hypothesis, we found that WWP2 is expressed in epithelial tissues that express ENaC, as well as in a wide variety of other tissues. WWP2 contains four WW domains, three of which bound differentially to ENaC subunits. In contrast, all four human Nedd4-2 WW domains bound to ENaC. WWP2 inhibited ENaC when coexpressed in epithelia, requiring a direct interaction between the proteins; mutation of the ENaC PY motifs abolished inhibition. Thus expression, binding, and functional data all suggest that WWP2 is a candidate to regulate ENaC-mediated Na(+) transport in epithelia.
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PMID:Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel. 1216 93

The epithelial sodium channel (ENaC) present in the kidney collecting duct, distal colon, and the lung is responsible for salt reabsorption and whole body volume regulation. It is composed of three homologous subunits, alpha, beta, and gamma, and mutations to these subunits can lead to the salt wasting disease pseudohypoaldosteronism type I, associated with decreased channel density at the plasma membrane or to the hypertensive disorder, Liddle's syndrome, in which channel residency time at the plasma membrane is enhanced. Regulation of ENaC trafficking and turnover is therefore critical to sodium homeostasis. In this study we examined whether ENaC is present in the cholesterol-enriched microdomains commonly called lipid rafts, in the endogenously expressing A6 cell line. We demonstrate that a fraction of alpha, beta, and gamma ENaC is present in detergent-insoluble membranes, that subunits exist in membranes that float on discontinuous sucrose density gradients, and that methyl-beta-cyclodextrin treatment causes a redistribution of ENaC subunits to higher density membranes. Furthermore, chronic aldosterone stimulation results in a shift in the membrane density of all three subunits. Biotinylation of apical membrane proteins revealed that ENaC is present in lipid rafts on the plasma membrane. In conclusion, these results show that ENaC is present in lipid rafts both intracellularly and on the cell surface. Raft association may be important for trafficking and/or function of the channel.
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PMID:Endogenously expressed epithelial sodium channel is present in lipid rafts in A6 cells. 1216 33

Hypertension is a substantial public health problem affecting about 25% of the population in industrialized societies. The disorder is responsible for many common causes of morbidity and mortality. Despite the important role of hypertension as a cause of disease, its pathogenesis remains largely unknown. The application of genetic approaches to rare monogenic (Mendelian) forms of hypertension and hypotension has begun to delineate molecular pathways underlying human blood pressure variation, defining disease pathogenesis and identifying targets for therapeutic intervention. In all cases the pathophysiology is altered net renal salt reabsorption. Mutations are either affecting circulating mineralocorticoid hormones or renal ion channels and transporters. Examples are glucocorticoid-remediable aldosteronism (GRA), Liddle's syndrome, the syndrome of hypertension exacerbated in pregnancy, and apparent mineralocorticoid-excess (AME). Recently, alterations in genes of a novel serine-threonine kinase family (WNK1 and WNK4) were identified causing pseudohypoaldosteronism type II. The molecular pathway of this syndrome remains unclear. Additionally, there is the syndrome of hypertension associated with brachydactyly type E (Bilginturan's syndrome), for which the molecular mechanism has yet to be identified.
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PMID:The molecular basis of hypertension. 1240 28

The epithelial sodium channel (ENaC) is a membrane protein made of three different but homologous subunits (a, b, and g) present in the apical membrane of epithelial cells of, for example, the distal nephron. This channel is responsible for salt reabsorption in the kidney and can cause human diseases by increasing channel function in Liddle's syndrome, a form of hereditary hypertension, or by decreasing channel function in pseudohypoaldosteronism type I, a salt-wasting disease in infancy. This review briefly discusses recent advances in understanding the implication of ENaC in Liddle's syndrome and in pseudohypoaldosteronism type I, both caused by mutations in the SCNN1 (ENaC) genes. Furthermore, it is still an open question to which extent SCNN1 genes coding for ENaC might be implicated in essential hypertension. The development of Scnn1 genetically engineered mouse models will provide the opportunity to test the effect of environmental factors, like salt intake, on the development of this kind of salt- sensitive hypertension.
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PMID:Epithelial sodium channel, salt intake, and hypertension. 1253 Sep 30

hNedd4 and Rsp5p are orthologous ubiquitin ligases that contain a catalytic Hect domain, a C2 domain and multiple WW domains that mediate interactions with proteins. hNedd4 associates with the epithelial sodium channel and mutations disrupting this interaction lead to Liddle's syndrome, a heritable hypertension. Yeast Rsp5p ubiquitinates plasma membrane receptors and transporters and regulates their endocytosis. To determine whether the human enzyme has activity in yeast, hNEDD4 was expressed in yeast from the RSP5 or GAL1/10 promoters. Ectopic hNedd4 improved the growth and partially suppressed the endocytosis defect of rsp5 mutant cells, although it did not restore the viability of the rsp5-delta strain. Wild-type cells harboring hNedd4 grew better at elevated temperature and on media containing cycloheximide. In contrast, hNedd4 WW domain mutants inhibited the growth of yeast when expressed at high levels. Our results show that hNedd4 affects cell growth, endocytosis and cycloheximide tolerance of yeast cells.
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PMID:Functional analysis of the human orthologue of the RSP5-encoded ubiquitin protein ligase, hNedd4, in yeast. 1268 39

Four types of monogenic hypertension belong to the group of mineralocorticoid hypertension, which are characterized by high renal water and sodium retention and resulting suppression of plasma renin activity (PRA), high urinary potassium secretion and consecutive low plasma potassium:1. increased production of the hormone aldosterone: glucocorticoid-remediable aldosteronism (GRH), 2. prereceptor disorder with loss of selectivity of the mineralocorticoid receptor: apparent mineralocorticoid excess (AME), 3. receptor disorder with constitutive activation of the mineralocorticoid receptor: "Geller syndrome", 4. postreceptor disorder with enhanced function of the epithelial sodium channel: Liddle's syndrome. While in GRH high synthesis of aldosterone results in high plasma aldosterone and low PRA, in the primary renal malfunctions of the AME, constitutive activation of the mineralocorticoid receptor and the Liddle's syndrome both plasma aldosterone and PRA are low. These forms of hypertension are rather rare in their complete expression, but they point to candidate genes whose mutations may predispose to hypertension. A point mutation of the ENaC beta-subunit (T594M) occurs rather frequent in people of African origin, with 5%. Therefore it is suggested to analyze the genotype of black hypertensive patients as a prerequisite for a rational amiloride therapy. Contrarily, the rather frequent (A[2139]G) polymorphism of the promoter of the alpha-subunit is supposed to mark a lower risk of hypertension. Mutations in the serine-threonine kinases WNK1 or WNK4 cause pseudohypoaldosteronism type II. WNK1 and WNK4 are expressed in the distal part of the nephron. Stimulation of sodium reabsorption by aldosterone is normal but without influence on hyperkalemia. An extrarenal disorder is suggested to be the cause of autosomal-dominant hypertension with brachydactyly: the patients react with a severely impaired baroreflex und show neurovascular contact. The mutation causing this syndrome is not known.
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PMID:[Monogenic hypertension]. 1271 44

Success in the search for genes that cause or contribute to hypertension susceptibility has been limited to a few rare Mendelian forms of hypertension (glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and Liddle's syndrome). Our well-reasoned efforts to assess candidate genes in critical pathways known to be involved in blood pressure regulation have not been as productive in complex genetic cases of hypertension. These cases involve both genetic and environmental determinants. The most frequently used approach to the identification of hypertension genes involves genetic association studies, which are population based and compare cases and controls. Linkage analyses are also used but require family data. While much effort is spent identifying new markers and candidate genes, it is important to periodically determine which findings of linkage or association are confirmed in order to advance our quest to identify hypertension genes. In this review, the status of the assessment of the HSD11B2 gene is reviewed. In addition, data supporting the need to assess the mitochondrial genome, the other human genome, in hypertension susceptibility are reviewed.
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PMID:Genetics of the kidney and hypertension. 1272 62

Liddle's syndrome is a monogenic form of hypertension caused by mutations in the PY motif of the COOH terminus of beta- and gamma-epithelial Na+ channel (ENaC) subunits. These mutations lead to retention of active channels at the cell surface. Because of the critical role of this PY motif in the stability of ENaCs at the cell surface, we have investigated its contribution to the ENaC response to aldosterone and vasopressin. Mutants of the PY motif in beta- and gamma-ENaC subunits (beta-Y618A, beta-P616L, beta-R564stop, and gamma-K570stop) were stably expressed by retroviral gene transfer in a renal cortical collecting duct cell line (mpkCCDcl4), and transepithelial Na+ transport was assessed by measurements of the benzamil-sensitive short-circuit current (Isc). Cells that express ENaC mutants of the PY motif showed a five- to sixfold higher basal Isc compared with control cells and responded to stimulation by aldosterone (10(-6) M) or vasopressin (10(-9) M) with a further increase in Isc. The rates of the initial increases in Isc after aldosterone or vasopressin stimulation were comparable in cells transduced with wild-type and mutant ENaCs, but reversal of the effects of aldosterone and vasopressin was slower in cells that expressed the ENaC mutants. The conserved sensitivity of ENaC mutants to stimulation by aldosterone and vasopressin together with the prolonged activity at the cell surface likely contribute to the increased Na+ absorption in the distal nephron of patients with Liddle's syndrome.
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PMID:Epithelial Na+ channel mutants causing Liddle's syndrome retain ability to respond to aldosterone and vasopressin. 1275 27


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