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

The epithelial Na(+) channel (ENaC), which plays an essential role in renal Na(+) handling, is composed of three subunits (alpha beta gamma), each containing a conserved PY motif at the C terminus. In Liddle's syndrome, an inherited form of salt-sensitive hypertension, the PY motifs of either beta or gamma ENaC are deleted or modified. We have recently shown that a ubiquitin-protein ligase Nedd4 binds via its WW domains to these PY motifs on ENaC, that ENaC is regulated by ubiquitination, and that Xenopus laevis Nedd4 (xNedd4) controls the cell surface pool of ENaC when coexpressed in Xenopus oocytes. Interestingly, Na(+) transporting cells, derived from mouse cortical collecting duct, express two different Nedd4 isoforms, which we have termed mNedd4-1 and mNedd4-2. Only mNedd4-2, which is orthologous to xNedd4, but not mNedd4-1, is able to regulate ENaC activity, and this property correlates with the capability to bind to the ENaC complex. Hence, Nedd4-2 may be encoded by a novel susceptibility gene for arterial hypertension.
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PMID:Liddle's syndrome: a novel mouse Nedd4 isoform regulates the activity of the epithelial Na(+) channel. 1147 28

Liddle's syndrome is a rare form of autosomal-dominant salt-sensitive hypertension. Constitutive activation of the amiloride-sensitive distal renal epithelial sodium channel (ENaC) is essential for salt-sensitive hypertension. Recently, several DNA analysis studies have indicated that there is a mutation of C-terminus of either the beta or y subunit. We sequenced the C-termini of the beta and -gamma subunits of the ENaC in a Japanese family with hypertension and hypopotassemia without excess minerarocorticoids, clinically diagnosed as Liddle's syndrome. The mutation of the ENaC of this family was beta R564X. Since such case seem to be rare in the literature, detailed data are shown in this report.
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PMID:A family with liddle's syndrome caused by a mutation in the beta subunit of the epithelial sodium channel. 1147 29

The importance of hypertension in the pediatric population is not as well appreciated as in adults. This might be related in part to the lower prevalence of high blood pressure in this age group. As with height and weight, blood pressure increases with age during childhood. The underlying causes of significant hypertension in children differ considerably from those in adults: while the prevalence of hypertension in pediatrics is lower than in adults, clinically identifiable causes of hypertension are common. Abnormalities in steroid biosynthesis have been known for years to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients, hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. Recently, the molecular basis of four forms of severe hypertension transmitted on an autosomal basis has been elucidated: (a) the glucocorticoid-remediable aldosteronism (GRA), (b) the syndrome of apparent mineralocorticoid excess (AME), (c) activating mutation of the mineralocorticoid receptor and (d) Liddle's syndrome. All these conditions are characterized primarily by low or low-normal plasma renin, normal or low serum potassium and salt-sensitive hypertension, indicating an increased mineralocorticoid effect. These forms of juvenile hypertension are a consequence of abnormal biosynthesis, metabolism or action of steroid hormones: (a) GRA is due to expression of a chimeric gene produced by fusion of 11beta-hydroxylase aldosterone-synthase genes. Expression of the chimeric enzyme occurs in the zona fasciculata of the adrenal cortex under the control of ACTH and can be suppressed by administration of glucocorticoids. (b) AME is caused by mutations of the 11beta-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolizes cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor (MR) from occupation by glucocorticoids. (c) The activating mutation of the MR results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups becoming potent agonists. (d) Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption. With the advent of molecular biology in clinical practice it has become evident that some genetic defect may present with a more discrete phenotype, with only moderate hypertension with or without hypokalemia as presenting feature. Considering that hypertension in children and adolescents is often 'nonessential', a search for disorders should be integral part of the diagnostic work-up in young patients with hypertension.
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PMID:Juvenile hypertension, the role of genetically altered steroid metabolism. 1174 Jan 42

Human hypertension is a common and complex disease and is associated with diabetes, cardiovascular, and renal disease. Therefore, it is important to understand the genetic basis of this disease. Specific genetic mutations leading to monogenic forms of hypertension have been identified in Liddle's syndrome and glucocorticoid-remediable hypertension and in some syndromes in which blood pressure is lowered. Because essential hypertension is a polygenic disease, elucidating a genotype that is causally related to essential hypertension will be difficult. To date, no genotype has been conclusively linked to essential hypertension except in certain populations. However, there has been progress in finding genetic variations that are associated with hypertension in patients with components of the metabolic syndrome (or Syndrome X). Future discoveries in this area should enhance our ability to intervene earlier and more effectively and therefore lessen the complications of this common disease.
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PMID:The genetics of human hypertension. 1178 66

Hypertension affects 20% to 25% of the adult population. Most patients are diagnosed as having essential or primary hypertension. Up to 10% to 15% have an identifiable cause and many of those have an adrenal basis. The identification of an adrenal cause of hypertension provides an opportunity for a targeted therapeutic intervention. Mineralocorticoid hypertension refers to hypertension caused by increased sodium and water retention by the kidney, expansion of the extracellular fluid compartment, and direct effects on the vasculature and circumventricular areas of the central nervous system (CNS), which result in elevation of blood pressure. The most common form of mineralocorticoid hypertension (MCH) is primary hyperaldosteronism (PA). In the past decade, significant advances have been made in our understanding of the pathogenesis of low-renin hypertension with the elucidation of the genetic basis and characterization of 3 forms of monogenic hypertension: glucocorticoid-remediable aldosteronism, syndrome of apparent mineralocorticoid excess, and Liddle's syndrome. This article focuses attention on the role of steroid hormones in the pathogenesis of hypertension and outlines the pathophysiology of the different forms of adrenal hypertension.
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PMID:Pathophysiology of adrenal hypertension. 1178 68

The activity of the epithelial Na(+) channel (ENaC) is required for the maintenance of salt and water balance in the body. Channel activity is regulated by the ubiquitin-protein ligase Nedd4 ['neuronal precursor cell-expressed developmentally down-regulated (gene 4)'] that interacts with the channel via its WW domains. Mutations in channel subunits that disrupt this interaction cause Liddle's syndrome, a severe inherited form of hypertension. In previous studies we showed that WW domains 2, 3 and 4 of human Nedd4 bound to the human ENaC (hENaC) subunits, whereas WW domain 1 did not. Here we extend this observation to determine the binding affinities of the human Nedd4 WW domains for hENaC C-terminal peptides. We show that WW domains 2, 3 and 4 bind with differing affinities to Na(+) channel subunit peptides. WW domain 3 has the highest affinity and we predict that WW domain 3 contributes most of the binding because a construct containing the three WW domains bound no better than WW domain 3 alone. Further, a single amino acid change (Arg(165)-->Thr) in WW domain 1 enables binding to the alpha subunit of the channel to occur, with an affinity comparable with that of WW domain 4. Differential binding propensities between the various WW domains and Na(+) channel subunit peptides are explained on the basis of quantitative structural modelling of the complexes and their isolated components.
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PMID:A single WW domain is the predominant mediator of the interaction between the human ubiquitin-protein ligase Nedd4 and the human epithelial sodium channel. 1180 77

The epithelial sodium channel (ENaC) expressed in aldosterone-responsive epithelial cells of the kidney and colon plays a critical role in the control of sodium balance, blood volume, and blood pressure. In lung, ENaC has a distinct role in controlling the ionic composition of the air-liquid interface and thus the rate of mucociliary transport. Loss-of-function mutations in ENaC cause a severe salt-wasting syndrome in human pseudohypoaldosteronism type 1 (PHA-1). Gain-of-function mutations in ENaC beta and gamma subunits cause pseudoaldosteronism (Liddle's syndrome), a severe form of salt-sensitive hypertension. This review discusses genetically defined forms of a salt sensitivity and salt resistance in human monogenic diseases and in animal models mimicking PHA-1 or Liddle's syndrome. The complex interaction between genetic factors (ENaC mutations) and the risk factor (salt intake) can now be studied experimentally. The role of single-nucleotide polymorphisms (SNPs) in determining salt sensitivity or salt resistance in general populations is one of the main challenges of the post-genomic era.
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PMID:Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. 1182 91

Monogenic or Mendelian forms of hypertension have ushered in a revolution in our knowledge. If we add information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid-remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the beta and gamma subunits of ENaC cause Liddle's syndrome. Loss-of-function mutations in all 3 subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all 3 subunits can be mutated, causing either hyper- or hypotension. Three loci have been described for Gordon's syndrome, pseudohypoaldosteronism type II; 2 members of the WNK (with no ly sine K) serine-threonine kinase family have recently been found to be responsible. Autosomal-dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. The elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.
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PMID:Monogenic forms of human hypertension. 1189 1

The epithelial Na+ channel (ENaC) forms the pathway for Na+ absorption in the kidney collecting duct and other epithelia. Dominant gain-of-function mutations cause Liddle's syndrome, an inherited form of hypertension resulting from excessive renal Na+ absorption. Conversely, loss-of-function mutations cause pseudohypoaldosteronism type I, a disorder of salt wasting and hypotension. Thus, ENaC has a critical role in the maintenance of Na+ homeostasis and blood pressure control. Altered Na+ absorption in the lung may also contribute to the pathogenesis of cystic fibrosis. Epithelial Na+ absorption is regulated in large part by mechanisms that control the expression of ENaC at the cell surface. Nedd4, a ubiquitin protein ligase, binds to ENaC and targets the channel for endocytosis and degradation. Liddle's syndrome mutations disrupt the interaction between ENaC and Nedd4, resulting in an increase in the number of ENaC channels at the cell surface. Aldosterone and vasopressin also regulate Na+ absorption to defend against hypotension and hypovolemia. Both hormones increase the expression of ENaC at the cell surface. The goal of this review is to summarize recent data on the regulation of ENaC expression at the cell surface.
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PMID:The epithelial Na+ channel: cell surface insertion and retrieval in Na+ homeostasis and hypertension. 1194 47

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


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