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 epithelial Na(+) channel (ENaC) is regulated by the ubiquitin-protein ligase Nedd4-2 via interaction with ENaC PY-motifs. These PY-motifs are mutated/deleted in Liddle's syndrome, resulting in elevated Na(+) reabsorption and hypertension explained partly by impaired ENaC-Nedd4-2 interaction. We hypothesized that Nedd4-2 is a susceptibility gene for hypertension and screened 856 renal patients and healthy controls for mutations in a subset of exons of the human Nedd4-2 gene that are relevant for ENaC regulation by PCR/single-strand conformational polymorphism. Several variants were identified, and one nonsynonymous mutation (Nedd4-2-P355L) was further characterized. This mutation next to the 3' donor site of exon 15 does not affect in vitro splicing of Nedd4-2 mRNA. However, in the Xenopus oocyte expression system, Nedd4-2-P355L-dependent ENaC inhibition was weaker compared with the wild type (Nedd4-2-WT), and this difference depended on the presence of intact PY-motifs on ENaC. This could not be explained by the amount of wild type or mutant Nedd4-2 coimmunoprecipitating with ENaC. When the phosphorylation level of human Nedd4-2 Ser(448) (known to be phosphorylated by the Sgk1 kinase) was determined with a specific anti-pSer(448) antibody, we observed stronger basal phosphorylation of Nedd4-2-P355L. Both the phosphorylation level and the accompanying amiloride-sensitive Na(+) currents could be further enhanced to approximately the same levels by coexpressing Sgk1. In addition, the role of the two other putative Sgk1 phosphorylation sites (S342 and T367) appears also to be affected by the P355L mutation. The differential phosphorylation status between wild-type and mutant Nedd4-2 provides an explanation for the different potential to inhibit ENaC activity.
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PMID:A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation in Xenopus laevis oocytes. 1514 Jul 63

Genetic analysis has demonstrated that Na absorption in the aldosterone-sensitive distal nephron (ASDN) critically determines extracellular blood volume and blood pressure variations. The epithelial sodium channel (ENaC) represents the main transport pathway for Na+ absorption in the ASDN, in particular in the connecting tubule (CNT), which shows the highest capacity for ENaC-mediated Na+ absorption. Gain-of-function mutations of ENaC causing hypertension target an intracellular proline-rich sequence involved in the control of ENaC activity at the cell surface. In animal models, these ENaC mutations exacerbate Na+ transport in response to aldosterone, an effect that likely plays an important role in the development of volume expansion and hypertension. Recent studies of the functional consequences of mutations in genes controlling Na+ absorption in the ASDN provide a new understanding of the molecular and cellular mechanisms underlying the pathogenesis of salt-sensitive hypertension.
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PMID:The epithelial sodium channel: from molecule to disease. 1514 50

The epithelial sodium channel (ENaC) has a central role in sodium transport across membranes. It is expressed on the apical cell surface of renal tubular epithelia and also on other aldosterone-responsive epithelial cells. In the kidney, ENaC contributes to the regulation of blood pressure via changes in sodium balance and blood volume. Rare monogenetic disorders associated with hypertension have been described, such as Liddle syndrome, which gives rise to increased sodium reabsorption in the kidney via increased ENaC activity. There are many other variants in the genes encoding ENaC subunits, some of which occur with sufficient frequency as to be termed polymorphic variants. The Thr594Met polymorphism of the ENaC beta-subunit gene SCNN1B occurs exclusively in Black individuals, with a frequency of 6-8% in those with hypertension. It increases cAMP mediated ENaC sodium current in affected B lymphocytes, and has been associated with hypertension in a Black South London population. There is preliminary evidence that amiloride is effective as monotherapy in hypertensive individuals with the Thr594Met polymorphism and in patients with resistant hypertension, who have evidence of increased amiloride-sensitive sodium channel activity. If these preliminary studies are corroborated in larger studies, then amiloride may provide an important new strategy for blood pressure control in selected individuals.
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PMID:The epithelial sodium channel in hypertension: genetic heterogeneity and implications for treatment with amiloride. 1517 97

Mechanosensitive ion channels are thought to mediate stretch-induced contraction in vascular smooth muscle cells (VSMCs); however, the molecular identity of the mechanosensitive ion channel complex is unknown. Although recent reports suggest degenerin/epithelial Na+ channel (DEG/ENaC) proteins may be mechanosensors in sensory neurons, their role as mechanosensors in vascular tissue has not been examined. We first tested whether DEG/ENaC subunits are expressed in cerebral blood vessels and VSMCs and then examined their role as mechanosensors in mediating the myogenic response in intact blood vessels. Using RT-PCR, we found ENaC transcripts expressed in rat cerebral arteries and freshly dissociated rat cerebral VSMCs. We also detected ENaC expression in isolated blood vessels and VSMCs by immunoblotting and immunolocalization. Moreover, inhibition of ENaC with amiloride (1 micromol/L) and benzamil (30 nmol/L, 1 micromol), an amiloride analog, blocked myogenic constriction in isolated rat cerebral arteries. These data suggest that DEG/ENaC proteins are required for vessel responses to pressure and are consistent with the evolutionary conservation of mechanosensory function of DEG/ENaC proteins.
Hypertension 2004 Nov
PMID:Degenerin/epithelial Na+ channel proteins: components of a vascular mechanosensor. 1538 80

Liddle's syndrome is an autosomal dominant form of salt-sensitive hypertension and has been shown to be caused by missense or frameshift mutations in the amiloride-sensitive epithelial sodium channel (ENaC), which is composed of three subunits: alpha, beta, and gamma. All disease mutations either remove or alter amino acids of the target proline-rich PPPxY sequence (PY motif) of beta- or gamma-ENaC and result in increased channel activity. In this report, we present a family with Liddle's syndrome whose abnormality is caused by a novel missense mutation, P616R, in the PY motif of the betaENaC. Functional studies using the P616R mutant expressed in Xenopus oocytes showed an approximately 6-fold increase in the amiloride-sensitive sodium channel activity compared with that of the wild type. These findings provide additional clinical evidence that a conserved PY motif is critically important for the regulation of ENaC activity.
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PMID:Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit. 1548 78

Liddle's syndrome is a genetic form of hypertension linked to Na(+) retention caused by activating mutations in the COOH terminus of the beta or gamma subunit of the epithelial sodium channel (ENaC). In this study, we used the short-circuit current (I(sc)) method to investigate the effects of deamino-8-d-arginine vasopressin (dDAVP) on Na(+) and Cl(-) fluxes in primary cultures of cortical collecting ducts (CCDs) microdissected from the kidneys of mice with Liddle's syndrome carrying a stop codon mutation, corresponding to the beta-ENaC R(566) stop mutation (L) found in the original pedigree. Compared to wild-type (+/+) CCD cells, untreated L/+ and L/L CCD cells exhibited 2.7- and 4.2-fold increases, respectively, in amiloride-sensitive (Ams) I(sc), reflecting ENaC-dependent Na(+) absorption. Short-term incubation with dDAVP caused a rapid and significant increase (approximately 2-fold) in Ams I(sc) in +/+, but not in L/+ or L/L CCD cells. In sharp contrast, dDAVP induced a greater increase in 5-nitro-2-(3-phenylpropamino)benzoate (NPPB)-inhibited apical Cl(-) currents in amiloride-treated L/L and L/+ cells than in their +/+ counterparts. I(sc) recordings performed under apical ion substituted conditions revealed that the dDAVP-stimulated apical secretion of Cl(-), which was absent in cultured CCDs lacking CFTR, was 1.8-fold greater in L/+ and 3.7-fold greater in L/L CCD cells than in their +/+ CCD counterparts. After the basal membrane had been permeabilized with nystatin and a basal-to-apical Cl(-) gradient had been imposed, dDAVP also stimulated larger Cl(-) currents across L/L and L/+ CCD layers than +/+ CCD layers. These findings demonstrate that vasopressin stimulates greater apical CFTR Cl(-) conductance in the renal CCD cells of mice with Liddle's syndrome than in wild-type mice. This effect could contribute to the enhanced NaCl reabsorption observed in the distal nephron of patients with Liddle's syndrome.
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PMID:Vasopressin-stimulated CFTR Cl- currents are increased in the renal collecting duct cells of a mouse model of Liddle's syndrome. 1551 33

Aldosterone plays a pivotal role in NaCl and K(+) homeostasis by stimulation of Na(+) reabsorption and K(+) secretion in the aldosterone-sensitive distal nephron (ASDN). Recent studies demonstrated that the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by aldosterone in the ASDN and that polymorphisms of the kinase associate with arterial blood pressure in normotensive subjects. This review discusses the role of Sgk1 in NaCl and K(+) homeostasis as evidenced by in vivo studies, including those in Sgk1-deficient mice. The studies indicate that Sgk1 is not absolutely required for Na(+) reabsorption and K(+) secretion in the ASDN. On a standard NaCl and K(+) diet, modestly enhanced plasma aldosterone concentrations appear sufficient to establish a compensated phenotype in the absence of Sgk1. The kinase is necessary, however, for upregulation of transcellular Na(+) reabsorption in the ASDN. This may involve Sgk1-mediated stimulation of basolateral Na(+)-K(+)-ATPase as well as retention of epithelial Na(+) channel, ENaC, in the apical membrane. Such an upregulation is a prerequisite for adequate adaptation of 1) renal NaCl reabsorption during restricted dietary NaCl intake, as well as 2) K(+) secretion in response to enhanced K(+) intake. Thus gain-of-function mutations of Sgk1 are expected to result in renal NaCl retention and enhanced K(+) secretion. Further studies are required to elucidate renal and nonrenal aldosterone-induced effects of Sgk1, the role of other Sgk1 activators, as well as the link of Sgk1 polymorphisms to arterial hypertension in humans.
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PMID:Role of Sgk1 in salt and potassium homeostasis. 1559 Sep 90

The so-called essential hypertension is not a single entity but a mixed bag with several polygenic quantitative traits acting in concert in different combinations in different individuals. This review collates all published information from different centres using different approaches to identify candidate genes in human hypertension. 1) gene targeting approach in animal models of HT (Smithies and Maeda, 1995); 2) identification of 874 candidate SNPs in 75 candidate genes for human HT (Halushka et al, 1999); 3) comparative genomic approach translating QTLs between rat and human HT, to identify 26 chromosome regions on 16 autosomes (Stoll M et al, 2000); 4) Ten centimorgan genome-wide scan done on 2010 affected sibling pairs drawn from 1599 severely hypertensive families (Caulfield et al, 2003). The molecular mechanisms of various molecules involved in the homeostasis of blood pressure are discussed. NO, O2, PG12, EDHF, endothelin, IL-6, selectin, phospholipase A2G1B, BH4, SOD, IRS-1, adrenomedullin, PAMP, CGRP, ANP, bradykinin and bombesin; adducin alpha, beta, gamma, SAH, renin, angiotensinogen. angiotensin II, aldosterone CYP11B1, mineralocorticoid receptors, 11betaHSD, DBH, PNMT, beta2adrenoreceptors, and genes related to ion transport-sodium-lithium cotransporters, ENaC, NaCl cotransporters NKCC2, KCNJ and NaKATPase. Altered gene expression in fetus due to maternal malnutrition also "programmes" for adult hypertension.
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PMID:Hypertension: molecular approach. 1563 21

The ubiquitin E3 protein ligase Nedd4-2 is a physiological regulator of the epithelial sodium channel ENaC, which is essential for transepithelial Na+ transport and is linked to Liddle's syndrome, an autosomal dominant disorder of human salt-sensitive hypertension. Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (Sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of ENaC. We report here that 14-3-3 proteins participate in this regulatory process through a direct interaction with a phosphorylated form of human Nedd4-2 (a human gene product of KIAA0439, termed hNedd4-2). The interaction is dependent on Sgk1-catalyzed phosphorylation of hNedd4-2 at Ser-468. We found that this interaction preserved the activity of the Sgk1-stimulated ENaC-dependent Na+ current while disrupting the interaction decreased ENaC density on the Xenopus laevis oocytes surface possibly by enhancing Nedd4-2-mediated ubiquitination that leads to ENaC degradation. Our findings suggest that 14-3-3 proteins modulate the cell surface density of ENaC cooperatively with Sgk1 kinase by maintaining hNedd4-2 in an inactive phosphorylated state.
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PMID:14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. 1567 82

The present study explores whether the development of hypertension in the Milan strain of rats (MHS) rats is preceded or paralleled by alterations of mRNA and/or protein levels of the major luminal Na+ transporters. MHS rats were studied at 23-25 days after birth; age-matched Milan normotensive (MNS) rats were used as controls. The glomerular filtration rate (GFR), measured by inulin clearance, was higher in MHS than in MNS rats, while the mean blood pressure was not different in the two strains of animals indicating that the MHS rats were still in the prehypertensive state. Type 3 sodium/hydrogen exchanger (NHE3), bumetanide-sensitive sodium-potassium-2 chloride cotransporter (NKCC2), sodium-chloride cotransporter (NCC) and alpha-ENaC mRNA abundances were quantified by competitive PCR. In MHS compared with MNS, mRNA abundance was unchanged for NHE3 in proximal tubules, higher for NKCC2 in medullary thick ascending limbs of Henle's loops (TAL) and lower for NCC in distal convoluted tubules (DCT) and for alpha-ENaC along collecting ducts (CD). Western blot experiments revealed 1) unchanged NHE3; 2) a significant increase in NKCC2 in the outer medulla; 3) a significant decrease in NCC in the renal cortex and of alpha-ENaC in both the renal cortex and outer medulla, whereas beta- and gamma-ENaC remained unchanged. These data indicate that, in MHS rats, there is a strong upregulation of NKCC2 along the TAL associated with increased GFR, robust inhibition of NCC cotransporter along the DCT and modest downregulation of alpha-ENaC along the CD. The interplay of the various Na+ transporters may well explain why, at this age, the rats are still in the prehypertensive state.
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PMID:Altered expression of renal apical plasma membrane Na+ transporters in the early phase of genetic hypertension. 1568 46


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