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

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

Angiotensin (Ang) II directly stimulates epithelial sodium channel activity in the rabbit cortical collecting duct. Because Ang I and converting enzyme analogues might be present in the distal nephron, this raises the possibility of intraluminal generation of Ang II. Conversion of Ang I to Ang II was monitored by Ang II-dependent changes in intracellular sodium concentration as a reflection of sodium transport across the apical membrane. This involved imaging-based fluorescence microscopy with sodium-binding benzofuran isophthalate in isolated, perfused, cortical collecting-duct segments from rabbit kidney. Principal and intercalated cells were differentiated by rhodamine-conjugated peanut lectin. Control principal cell intracellular sodium concentration, during perfusion with 25 mmol/L NaCl and zero sodium in the bath plus monensin (10(-5) mol/L) averaged 5.8+/-0.14 mmol/L (n=156). The increase in intracellular sodium concentration, when luminal NaCl was increased from 25 to 150 mmol/L, was elevated by 3.5-fold in the presence of intraluminal Ang I (10(-6) mol/L). Also, the effects of Ang I on sodium transport were not significantly different from the effects of Ang II (10(-9) mol/L). Ang I was used in micromolar concentrations to ensure that there was sufficient substrate available for conversion to Ang II. Inhibition of the angiotensin-converting enzyme with captopril reduced the stimulatory effect of Ang I. These results suggest that intraluminal conversion of Ang I to Ang II can occur in the cortical collecting duct, resulting in enhanced apical sodium entry.
Hypertension 2003 Aug
PMID:Angiotensin I conversion to angiotensin II stimulates cortical collecting duct sodium transport. 1283 30

Hypertension with hypokalemia, metabolic alkalosis, and suppressed plasma renin activity defines mineralocorticoid hypertension. Mineralocorticoid hypertension is the consequence of an overactivity of the epithelial sodium channel expressed at the apical membrane of renal cells in the distal nephron. This is usually the case when the mineralocorticoid receptor is activated by its physiologic substrate aldosterone. The best known form of mineralocorticoid hypertension is an aldosterone-producing adrenal tumor leading to primary aldosteronism. Primary aldosteronism can also be caused by unilateral or bilateral adrenal hyperplasia and rarely adrenal carcinoma. Interestingly, most of the inherited monogenic disorders associated with hypertension involve an excessive activation of the mineralocorticoid axis. In some of these disorders, mineralocorticoid hypertension results from activation of the mineralocorticoid receptor by other steroids (cortisol, deoxycorticosterone), by primary activation of the receptor itself, or by constitutive overactivity of the renal epithelial sodium channel. The present review addresses the physiology and significance of the key players of the mineralocorticoid axis, placing emphasis on the conditions leading to mineralocorticoid hypertension.
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PMID:Forms of mineralocorticoid hypertension. 1285 54

1. The level of mRNA expression of epithelial sodium channel (ENaC) subunits was studied in a salt-dependent hypertensive rat strain (Sabra). These rats exhibit high vasopressin levels compared with their normotensive counterparts. We also investigated whether this expression is influenced by changes in the sodium intake/aldosterone axis or in the fluid intake/vasopressin axis. 2. A higher expression of beta- and gamma-subunit mRNA was found in salt-sensitive compared with salt-resistant rats on a normal salt diet. A high-sodium diet did not alter mRNA abundance in either substrain. In contrast, water supplementation in salt-sensitive rats fed the high-sodium diet induced a marked reduction in mRNA abundance of beta- and gamma-subunits. 3. The present study provides evidence that beta- and gamma-subunits of ENaC are differently expressed in the kidney of salt-sensitive and salt-resistant Sabra rats and that their abundance is regulated by vasopressin, not by sodium intake. These results are consistent with the hypothesis that increased vasopressin-dependent ENaC expression and activity may contribute to the pathogenesis of hypertension in salt-sensitive Sabra rats.
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PMID:Effect of salt and water intake on epithelial sodium channel mRNA abundance in the kidney of salt-sensitive Sabra rats. 1467 37

Regulation of the epithelial sodium channel (ENaC) is important for the long-term control of arterial blood pressure as evidenced by gain of function mutations of ENaC causing Liddle's syndrome, a rare form of hereditary arterial hypertension. In Xenopus laevis oocytes expressing ENaC a spontaneous decline of ENaC currents over time, so-called rundown, is commonly observed. Mechanisms involved in rundown may be physiologically relevant and may be related to feedback regulation of ENaC by intra- or extracellular Na+. We tested the effect of extracellular Na+ removal on ENaC rundown. Spontaneous rundown of ENaC was largely prevented by extracellular Na+ removal and was partially prevented by primaquine suggesting that it is due to endocytic channel retrieval. Liddle's syndrome mutation caused a reduced rate of rundown, and in oocytes expressing the mutated channel extracellular Na+ removal not only prevented rundown but even increased the ENaC currents (runup). Acute exposure to high extracellular Na+ drastically reduced whole-cell currents and surface expression of wild-type ENaC, while these effects were much smaller in ENaC with Liddle's syndrome mutation consistent with a stabilization of the mutated channel in the plasma membrane. Interestingly, the apparent intracellular Na+ concentration [Na+](i-app) was high (>60 mM) in ENaC-expressing oocytes but rundown was not associated with a further increase in [Na+](i-app). We conclude that the inhibitory effect of extracellular Na+ removal on rundown is due to an inhibition of endocytic ENaC retrieval.
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PMID:Extracellular Na+ removal attenuates rundown of the epithelial Na+-channel (ENaC) by reducing the rate of channel retrieval. 1470 95

High blood pressure occurs commonly in individuals of African origin, leading to an increased risk of cardiovascular and end-stage renal disease (ESRD). Black individuals frequently have low plasma renin activity, and their blood pressure responds well to salt reduction, suggesting that abnormalities in renal sodium handling may be important in the etiology of hypertension in this population. The epithelial sodium channel (ENaC) has a central role in sodium transport across membranes, and in the kidney it contributes to the regulation of blood pressure via changes in sodium balance and blood volume. Rare monogenetic disorders have been described in association with hypertension, such as Liddle's syndrome. In addition, other ENaC polymorphisms have also been described, some of which are more common in black individuals. The T594M polymorphism of ENaC occurs exclusively in black individuals and is associated with hypertension in a black South London population. There is preliminary evidence that amiloride is effective as monotherapy in hypertensives with the T594M polymorphism, and a further study is underway to determine whether this is indeed a safe and specific treatment. If so, then amiloride may provide an important new strategy for blood pressure control in affected black hypertensives.
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PMID:Genetic variation in the epithelial sodium channel: a risk factor for hypertension in people of African origin. 1473 May 41

Studies on Mendelian hypertension have provided great insight into mechanisms causing hypertension. Mineralocorticoid synthesis and degradation, the mineralocorticoid receptor, sodium channel resorptive mechanisms, and regulation of the thiazide-sensitive sodium-chloride cotransporter have been shown to cause hypertension. Aberrant regulation of peripheral vascular resistance and circulatory regulation have not yet been proved but have been strongly implicated in Mendelian hypertension with brachydactyly. Hypertension as a complex genetic trait has proved more difficult because many genes are involved and the genes have much smaller effects. Association studies, linkage analyses, single nucleotide polymorphism analyses, synteny in animal models, and gene expression studies are the current tools and steady progress is being made.
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PMID:Present status of genetic mechanisms in hypertension. 1487 Oct 48

Hypertension is a compelling disease process that disproportionately affects African Americans. It is the single largest risk factor for cardiovascular disease in African Americans. The end organ manifestations of hypertension are striking and include higher rates of stroke, significantly increased renal disease including end-stage renal disease requiring dialysis, higher risk of left ventricular hypertrophy, and an associated higher risk of heart failure. The cause of these more aggressive end organ phenomena is likely multifactorial and includes a mix of genetic and environmental influences. Intriguing polymorphisms of the epithelial sodium channel are consistent with patterns of hypertension seen in African Americans. Obesity, especially in African-American women, may be closely related to hypertension as a result of sympathetic nervous system stimulation.
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PMID:Pathogenesis of hypertension in African Americans. 1487 54

Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies demonstrated the presence of these receptors in nonclassical locations, including the cardiovascular system. We tested the hypothesis whether endothelial cells respond to aldosterone with changes in cell volume, a measure for ion-mediated water movement across the cell membrane. By means of atomic force microscopy in fluid, we measured volume of adherent human umbilical venous endothelial cells exposed for 72 hours to 10 nmol/L aldosterone. Over this period of time, cells swell by approximately 18%. Aldosterone-induced swelling is prevented by 100 nmol/L of the mineralocorticoid receptor antagonist spironolactone, added to the primary endothelial cell culture. Aldosterone-treated cells dramatically shrink when 1 micromol/L of the diuretic amiloride is applied. Cells deprived of aldosterone do not respond to amiloride. Our conclusions are: (1) aldosterone leads to sustained cell swelling inhibited by administration of spironolactone or the sodium channel blocker amiloride; (2) cells respond to amiloride after aldosterone exposure; (3) renal diuretics act on endothelial cells; and (4) both amiloride and spironolactone could be useful for medical applications to prevent aldosterone-mediated endothelial dysfunction.
Hypertension 2004 May
PMID:Human endothelium: target for aldosterone. 1500 36


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