Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPXY motif that is believed to be important for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PPXY motif of either the beta or gamma subunits, has been shown to result in increased ENaC activity and arterial hypertension. Here we present evidence that N4WBP5A, a novel Nedd4/Nedd4-2-binding protein, is a potential regulator of ENaC. In Xenopus laevis oocytes N4WBP5A increases surface expression of ENaC by reducing the rate of ENaC retrieval. We further demonstrate that N4WBP5A prevents sodium feedback inhibition of ENaC possibly by interfering with the xNedd4-2-mediated regulation of ENaC. As N4WBP5A binds Nedd4/Nedd4-2 via PPXY motif/WW domain interactions and appears to be associated with specific intracellular vesicles, we propose that N4WBP5A functions by regulating Nedd4/Nedd4-2 availability and trafficking. Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo.
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PMID:Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein. 1205 Jan 53

The present study was intended to determine whether the long-term V2 receptor-mediated effects of vasopressin on sodium reabsorption in the renal collecting duct is an aggravating factor in salt-sensitive hypertension. Deoxycorticosterone acetate (DOCA)-salt hypertension was induced in uninephrectomized rats that had been chronically pretreated with a V2 agonist (dDAVP; 1-deamino-8D-arginine vasopressin; 0.6 microg/kg.d) or a V2 antagonist (SR121463, 3 mg/kg.d) or were untreated. Plasma osmolality and natremia were not significantly different in the groups. Blood pressure was significantly increased by dDAVP pretreatment (+11 mm Hg; P = 0.006), and this effect was exacerbated after DOCA-salt-induced hypertension (+17 mm Hg; P = 0.042). The dDAVP-treated rats had a lower hematocrit (40 +/- 2% vs. 47 +/- 1% and 45 +/- 2%) and markedly higher albuminuria (91 +/- 9 vs. 17 +/- 8 and 15 +/- 8 mg/d), mortality rate (50% vs. 0% and 0%), and cardiac and renal hypertrophy than the control and SR121463 groups. Histological renal lesions were worsened by V2 agonism and prevented by V2 antagonism. Renal mRNA expression of beta- and gamma-subunits of the epithelial sodium channel was significantly increased by dDAVP treatment (P < 0.05). These findings provide evidence that chronic stimulation of vasopressin V2 receptor raises basal blood pressure in rats and exacerbates the development of DOCA-salt hypertension, organ damage, and mortality. These effects could be due at least in part to the sustained stimulation of sodium reabsorption by epithelial sodium channel in the distal part of the nephron, which promotes sodium retention.
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PMID:Chronic V2 vasopressin receptor stimulation increases basal blood pressure and exacerbates deoxycorticosterone acetate-salt hypertension. 1207 11

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 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

We have tested 186 individuals from Ghana, 95 indigenous and 91 who have settled in the United Kingdom, for the presence of the T594M mutation in the beta-subunit of the epithelial sodium channel, which is associated with hypertension in black populations. The group living in Ghana had a mean age of 27 years and were normotensive, but had an increased frequency of the T allele compared to the London-based population. If this is reflected in larger studies, and the link with hypertension is maintained in the Ghanaian population, this mutation could be a significant cause of hypertension in Ghana.
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PMID:T594M mutation of the beta-subunit of the epithelial sodium channel in Ghanaian populations from Kumasi and London and a possible association with hypertension. 1218 79

Compared with whites, blacks appear to retain additional sodium that suppresses secretion of renin and aldosterone. The epithelial sodium channel (ENaC) is an aldosterone-regulated site for sodium reabsorption. ENaC activity could be higher in blacks, contributing to sodium retention or, alternatively, lower because of reduced stimulation by aldosterone. To examine the level of ENaC activity in blacks relative to whites, blood pressure (BP) responses to amiloride (5 mg/d), an inhibitor of ENaC, were measured in 20 black and 25 white normotensive young people. After 1 week, systolic BP decreased by 3.0+/-9.2 (SD) and diastolic by 2.8+/-8.3 mm Hg in the whites, whereas systolic BP increased by 2.5+/-7.1 and diastolic by 3.8+/-8.0 mm Hg in the blacks; the racial difference in the BP response was significant for both systolic (P=0.034) and diastolic BP (P=0.010). As ENaC activity increases, renal secretion of potassium increases proportionately, and in a larger sample of subjects, the urinary potassium excretion rate was lower in the blacks (n=301) than in the whites (n=461): 3.2+/-0.1 versus 3.8+/-0.1 mmol/mmol creatinine (P=0.0001). The concentration of serum potassium was higher in the blacks (n=81) than in the whites (n=167): 4.36+/-0.05 versus 4.21+/-0.03 (P=0.012). In summary, a favorable BP response to amiloride in the whites as well as the evidence for greater retention of potassium in the blacks is consistent with blacks having less ENaC activity than whites. We suggest that increased sodium retention in blacks occurring at other nephron sites suppresses aldosterone secretion and in turn ENaC function.
Hypertension 2002 Dec
PMID:Racial difference in the activity of the amiloride-sensitive epithelial sodium channel. 1246 77

Hypertension is the most prevalent, treatable risk factor for diseases of the heart, brain and kidneys. In this review, we discuss advances in understanding of the genetics of blood pressure regulation, the development of hypertensive complications and the pharmacodynamics of antihypertensive drug responses. Discovery of single gene mutations that cause hypertension or hypotension in humans suggests that the common final pathway for regulation of blood pressure level is via alterations in renal sodium handling. Based on a working hypothesis that common genetic variations contributing to blood pressure variation in the population may also act on this same pathway, we summarize supporting evidence emerging from linkage and selected association studies of candidate genes--including those encoding components of the renin-angiotensin-aldosterone system, the epithelial sodium channel, adrenoceptors, G protein subunits, and other cellular signaling mediators and modifiers. We proceed to distinguish ischemic target organ complications due to arteriolosclerotic changes of the microvasculature from those due to atherosclerosis involving larger conduit and capacitance arteries. Using the example of subcortical white matter ischemia of the brain, we propose that interindividual variation in the arteriolosclerotic complications is more likely than atherosclerotic complications to be related to the same genetic (and environmental) mechanisms that contribute to hypertension. We conclude by summarizing the state-of-the-art of antihypertensive pharmacogenetics, which has succeeded in rejecting the null hypothesis that genetic variation does not influence blood pressure or protective target organ responses to drug therapy. In each of the three areas covered in this review, we indicate the many remaining obstacles to the routine clinical use of genetic measurements in the diagnosis, evaluation and treatment of hypertension.
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PMID:Genetics of blood pressure, hypertensive complications, and antihypertensive drug responses. 1251 86

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

Serum and glucocorticoid-induced kinase 1 (SGK1) activates the epithelial sodium channel (eNaC) in tubules. We examined renal SGK1 abundance in salt-adaptation and in salt-sensitive hypertension. Sprague-Dawley and Dahl salt-sensitive rats were placed on either 8% or 0.3% NaCl diets for 10 days. Plasma aldosterone levels were approximately 2.5-fold greater on 0.3% versus 8% NaCl diets in both rat strains. Both serum and glucocorticoid-induced kinase 1 transcript and protein abundance were less (P<0.01) in Sprague-Dawley rats and greater (P<0.01) in Dahl salt-sensitive rats on 8% versus 0.3% NaCl diets. The cDNA sequences of serum and glucocorticoid-induced kinase 1 in both strains of rat were the same. The present results provide evidence that the abundance of serum and glucocorticoid-induced kinase 1 in rat kidney may play a role in salt adaptation and the pathogenesis of hypertension and suggests that aldosterone is not the primary inducer of SGK1 in the Sprague-Dawley rat.
Hypertension 2003 Apr
PMID:Dietary salt regulates renal SGK1 abundance: relevance to salt sensitivity in the Dahl rat. 1264 12

We carried out semiquantitative immunoblotting of kidney to identify apical sodium transporter proteins whose abundances are regulated by angiotensin II. In NaCl-restricted rats (0.5 mEq Na/200 g BW/d), the type 1 angiotensin II receptor (AT1 receptor) antagonist, candesartan, (1 mg/kg of body weight per day SC for 2 days) markedly decreased the abundance of the alpha subunit of the epithelial sodium channel (ENaC). This subunit has been shown to be rate-limiting for assembly of mature ENaC complexes. In addition, systemic infusion of angiotensin II increased alphaENaC protein abundance in rat kidney cortex. The decrease in alphaENaC protein abundance in response to AT1 receptor blockade was associated with a fall in alphaENaC mRNA abundance (real-time RT-PCR), consistent with transcriptionally mediated regulation. The effect of AT1 receptor blockade on alphaENaC expression was not blocked by spironolactone, suggesting a direct role of the AT1 receptor in regulation of alphaENaC gene expression. Candesartan administration was also found to increase the abundances of the beta and gamma subunits. The increase in beta and gammaENaC protein abundance was not associated with a significant increase in the renal abundances of the corresponding mRNAs, suggesting a posttranscriptional mechanism. Immunocytochemistry confirmed the increase in beta and gammaENaC protein abundance and demonstrated candesartan-induced ENaC internalization in collecting duct cells. The results support the view that the angiotensin II receptor regulates ENaC abundance, consistent with a role for angiotensin II in regulation of collecting duct function.
Hypertension 2003 May
PMID:Long-term regulation of ENaC expression in kidney by angiotensin II. 1268 79


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