A novel potent epithelial sodium channel blocker seems to be a safe and well-tolerated therapy in patients with symptoms of mild-to-moderate dry eye disease compared with placebo.

Recent studies suggest that the epithelial sodium channel (ENaC) is expressed in the endothelial cells. To test whether high salt affects the NO production via regulation of endothelial ENaC, human umbilical vein endothelial cells (HUVECs) were incubated in solutions containing either normal or high sodium (additional 20 mM NaCl). Our data showed that high sodium treatment significantly increased α-, β-, and γ-ENaC expression levels in HUVECs. Using the cell-attached patch-clamp technique, we demonstrated that high sodium treatment significantly increased ENaC open probability (PO). Moreover, nitric oxide synthase (eNOS) phosphorylation (Ser 1177) levels and NO production were significantly decreased by high sodium in HUVECs; the effects of high sodium on eNOS phosphorylation and NO production were inhibited by a specific ENaC blocker, amiloride. Our results showed that high sodium decreased AMP-activated kinase (AMPK) phosphorylation in endothelial cells. On the other hand, metformin, an ...

2015 Elsevier Inc. The epithelial sodium channel (ENaC) plays a critical role in maintaining Na+ homeostasis in various tissues throughout the body. An understanding of the structure of the ENaC subunits has been developed from homology modeling based on the related acid sensing ion channel 1 (ASIC1) protein structure, as well as electrophysiological approaches. However, ENaC has several notable functional differences compared to ASIC1, thereby providing justification for determination of its three-dimensional structure. Unfortunately, this goal remains elusive due to several experimental challenges. Of the subunits that comprise a physiological hetero-trimeric αβγENaC, the α-subunit is unique in that it is capable of forming a homo-trimeric structure that conducts Na+ ions. Despite functional and structural interest in αENaC, a key factor complicating structural studies has been its interaction with multiple other proteins, disrupting its homogeneity. In order to address this issue, a ...

The epithelial sodium channel (ENaC) is a protein located at the apical membrane of polarised epithelial cells, primarily expressed in the epithelia of the gastrointestinal tract, lungs and kidney. ENaCs main function is that of absorbing sodium and it is strongly involved in regulating and maintaining total-body salt and water homeostasis, acting as the rate-limiting step for sodium reabsorption into the body. Its activity, therefore, is crucial for determining blood volume and, as a consequence, blood pressure. The sorting and trafficking of ENaC to the apical membrane is a tightly controlled process, requiring the interaction of multiple proteins and organelles. Although ENaC has been well-characterised, there are certain aspects about its trafficking which need to be clarified, such as defining the many proteins involved in the recycling of the channel to and from the apical membrane. A potential, novel candidate involved in ENaC recycling is the retromer complex. This endosome-associated ...

Sigma-Aldrich offers abstracts and full-text articles by [Bettina Krueger, Ursula Schlötzer-Schrehardt, Silke Haerteis, Matthias Zenkel, Verena E Chankiewitz, Kerstin U Amann, Friedrich E Kruse, Christoph Korbmacher].

Principal Investigator：ONO Shuichi, Project Period (FY)：1997 - 1998, Research Category：Grant-in-Aid for Scientific Research (C), Section：一般, Research Field：Kidney internal medicine

In the present study, we confirmed ENaC expression in SDMAs, and we found that ENaC blockers reduced the contractile response to phenylephrine and serotonin. The EC50 values obtained in dose-response experiments with pharmacological ENaC inhibitors are similar to the published inhibition constant and IC50 values for ENaC in mammalian distal nephron segments and Xenopus oocytes expressing α, β, and γ ENaC (amiloride: 10 to 100 nmol/L; benzamil: 10 nmol/L).1,2 In addition, an amiloride derivative (ethyl isopropyl amiloride) did not affect the contractile response to phenylephrine. In situ hybridization and immunohistochemistry studies showed α, β, and γ ENaC expression in the tunica media and endothelial cells of SDMAs. In addition, amiloride-sensitive sodium currents were detected in primary cultures of mesenteric artery endothelial cells. These data indicate expression of all 3 of the ENaC subunits in SDMAs that would form trimeric channels with biophysical properties similar to the ...

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Sigma-Aldrich offers abstracts and full-text articles by [K J Coote, D Paisley, S Czarnecki, M Tweed, H Watson, A Young, R Sugar, M Vyas, N J Smith, U Baettig, P J Groot-Kormelink, M Gosling, R Lock, B Ethell, G Williams, A Schumacher, J Harris, W M Abraham, J Sabater, C T Poll, T Faller, S P Collingwood, H Danahay].

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Parion Sciences is developing P 1037 (VX 371), a long-acting inhaled epithelial sodium channel (ENaC) inhibitor, for the treatment of cystic fibrosis (CF) and

TGF-beta directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury ...

Statement of the problem: The epithelial sodium channels (ENaC) play an important role in regulation of blood pressure (BP). Although the genes are identical in Dahl salt sensitive (S) and Dahl salt resistant (R) rats, expression of ENaC subunits is increased in kidneys of S rats on high salt diet. Intracerebroventricular (icv) infusion of ENaC blocker benzamil prevents Na+ induced hypertension. It was not known whether ENaC subunits are expressed in the brain and whether or not brain ENaC plays a role in regulation of [Na+] in CNS. Hypothesis: 1. Epithelial sodium channels are expressed in the brain. 2. Expression of ENaC is increased in the kidneys and brain of Dahl S rats on high salt diet. 3. ENaC in the brain contributes to regulation of [Na+] in the CSF and brain interstitium. Methods of investigation: We studied expression and distribution of the ENaC subunits and assessed the effects of icv infusion of Na+-rich aCSF in Wistar rats or high salt diet in Dahl S rats in different areas of ...

TY - JOUR. T1 - Electrophysiology of Epithelial Sodium Channel (ENaC) Embedded in Supported Lipid Bilayer Using a Single Nanopore Chip. AU - Khan, Muhammad Shuja. AU - Dosoky, Noura Sayed. AU - Mustafa, Ghulam. AU - Patel, Darayas. AU - Berdiev, Bakhrom. AU - Williams, John Dalton. PY - 2017/11/28. Y1 - 2017/11/28. N2 - Nanopore-based technologies are highly adaptable supports for developing label-free sensor chips to characterize lipid bilayers, membrane proteins, and nucleotides. We utilized a single nanopore chip to study the electrophysiology of the epithelial Na+ channel (ENaC) incorporated in supported lipid membrane (SLM). An isolated nanopore was developed inside the silicon cavity followed by fusing large unilamellar vesicles (LUVs) of DPPS (1,2-dipalmitoyl-sn-glycero-3-phosphoserine) and DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine) to produce a solvent-free SLM with giga-ohm (Gω) sealed impedance. The presence and thickness of SLM on the nanopore chip were confirmed using ...

Opens the Highlight Feature Bar and highlights feature annotations from the FEATURES table of the record. The Highlight Feature Bar can be used to navigate to and highlight other features and provides links to display the highlighted region separately. Links in the FEATURES table will also highlight the corresponding region of the sequence. More... ...

TY - JOUR. T1 - The epithelial sodium channel in the Australian lungfish, Neoceratodus forsteri (Osteichthyes. T2 - Dipnoi). AU - Uchiyama, Minoru. AU - Maejima, Sho. AU - Yoshie, Sumio. AU - Kubo, Yoshihiro. AU - Konno, Norifumi. AU - Joss, Jean M P. PY - 2012. Y1 - 2012. N2 - Epithelial sodium channel (ENaC) is a Na+-selective, aldosterone-stimulated ion channel involved in sodium transport homeostasis. ENaC is rate-limiting for Na+ absorption in the epithelia of osmoregulatory organs of tetrapods. Although the ENaC/degenerin gene family is proposed to be present in metazoans, no orthologues or paralogues for ENaC have been found in the genome databases of teleosts. We studied full-length cDNA cloning and tissue distributions of ENaCα, β and γ subunits in the Australian lungfish, Neoceratodus forsteri, which is the closest living relative of tetrapods. Neoceratodus ENaC (nENaC) comprised three subunits: nENaCα, β and γ proteins. The nENaCα, β and γ subunits are closely related to ...

TY - JOUR. T1 - NVP-QBE170. T2 - An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia. AU - Coote, K. J.. AU - Paisley, D.. AU - Czarnecki, S.. AU - Tweed, M.. AU - Watson, H.. AU - Young, A.. AU - Sugar, R.. AU - Vyas, M.. AU - Smith, N. J.. AU - Baettig, U.. AU - Groot-Kormelink, P. J.. AU - Gosling, M.. AU - Lock, R.. AU - Ethell, B.. AU - Williams, G.. AU - Schumacher, A.. AU - Harris, J.. AU - Abraham, W. M.. AU - Sabater, J.. AU - Poll, C. T.. AU - Faller, T.. AU - Collingwood, S. P.. AU - Danahay, H.. N1 - Publisher Copyright: © 2015 The British Pharmacological Society. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.. PY - 2015/6/1. Y1 - 2015/6/1. N2 - Background and Purpose Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ...

Potassium-sparing diuretics, which block the epithelial sodium channel (ENaC), are widely prescribed for hypertension as a second-line drug in patients taking other diuretics (e.g. thiazide diuretics) and much less commonly prescribed as monotherapy. Therefore, it is essential to determine the effects of ENaC blockers on blood pressure (BP), heart rate and withdrawals due to adverse effects (WDAEs) when given as a first-line or second-line therapy. ...

NOS1-dependent negative feedback regulation of the epithelial sodium channel in the collecting duct. Am J Physiol Renal Physiol. 2014 Nov 12;:ajprenal.00596.2013 Authors: Hyndman KA, Bugaj V, Mironova E, Stockand JD, Pollock JS Abstract With an increase in urine flow there is a significant increase in shear stress against the renal epithelium including the inner medullary col...

Background/Seeks: The aim of this study was to evaluate the feasibility of -fetoprotein (AFP) as a diagnostic tool for hepatocellular carcinoma (HCC) in Korean patients. patients was 0.757. The sensitivity, specificity, and positive predictive value of AFP was 50.55%, 87.70%, and 80.43%, respectively, at a cut-off of 20 ng/mL; 37.70%, 95.90%, and 90.20%, respectively, at a cut-off of 100 ng/mL, and 30.05%, 97.27%, and 91.67%, respectively, at a cut-off of 200 ng/mL. A cut-off of 100 ng/mL was more sensitive than one of 200 ng/mL with equivalent specificity and positive predictive value. Conclusions: The cut-off AFP value for early-stage HCC was 17.4 ng/mL. Our study cautiously suggests that AFP has a role in the diagnosis of HCC, which the correct worth of AFP for the analysis of HCC may be 100 ng/mL instead of 548472-68-0 supplier 200 ng/mL. check or the Mann-Whitney check for continuous factors. Our research was made to compare the perfect cut-off ideals of AFP by increasing the amount of ...

Read Stimulation of ENaC Activity by Rosiglitazone is PPARγ-Dependent and Correlates with SGK1 Expression Increase, The Journal of Membrane Biology on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.

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TY - JOUR. T1 - A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. AU - Czikora, István. AU - Alli, Abdel. AU - Bao, Hui Fang. AU - Kaftan, David. AU - Sridhar, Supriya. AU - Apell, Hans Jürgen. AU - Gorshkov, Boris. AU - White, Richard. AU - Zimmermann, Astrid. AU - Wendel, Albrecht. AU - Pauly-Evers, Meike. AU - Hamacher, Jürg. AU - Garcia-Gabay, Irène. AU - Fischer, Bernhard. AU - Verin, Alexander. AU - Bagi, Zsolt. AU - Pittet, Jean Francois. AU - Shabbir, Waheed. AU - Lemmens-Gruber, Rosa. AU - Chakraborty, Trinad. AU - Lazrak, Ahmed. AU - Matthay, Michael A.. AU - Eaton, Douglas C.. AU - Lucas, Rudolf. PY - 2014/9/1. Y1 - 2014/9/1. N2 - Rationale: Alveolar liquid clearance is regulated by Na+ uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na+-K+-ATPase in type II alveolar epithelial cells. Dysfunction of these Na+ transporters during pulmonary inflammation can contribute to pulmonary ...

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 which is believed to be important for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4. Disruption of this interaction, as in Liddles syndrome, where mutations delete or alter the PPxY motif of either the beta or gamma subunits, has been proposed to result in increased ENaC activity. Here we present evidence that KIAA0439 protein, a close relative of Nedd4, is also a potential regulator of ENaC. We demonstrate that KIAA0439 WW domains bind all three ENaC subunits. We show that a recombinant KIAA0439 WW domain protein acts as a dominant negative mutant that can interfere with the Na(+)-dependent feedback inhibition of ENaC in whole-cell patch clamp experiments. We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC ...

Regulation of transepithelial sodium transport by corticosteroids occurs in two phases: early and delayed. The early phase involves the activation and translocation of pre-existing epithelial sodium channels (ENaC); whereas, the delayed phase involves the de novo synthesis of ENaC. An important regulator of the early phase is the serum-and glucocorticoid-inducible kinase (SGK1). The traditional view is that SGK1 is involved in the activation and translocation of ENaC, thereby regulating the early phase of ENaC activity. On the other hand, the possible involvement of SGK1 during the de novo synthesis of ENaC has not been studied. In Chapter 1 we report the role of SGK1 in the delayed phase of corticosteroid regulation of ENaC transcription in cortical collecting duct cells. Using polymerase chain reaction (PCR) we determined that cells over-expressing SGK1 (FL-SGK1) had significantly higher levels of α and βENaC mRNA as compared to cells expressing dominant negative SGK1 (K127M-SGK1). ENaC is a ...

Authors:. Chenguang Zhao, Jeff Crosby, Tinghong Lv, Dong Bai, Brett P. Monia, and Shuling Guo. Affiliations:. Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010 USA. What was your research question?. Previous studies show that the epithelial sodium channel (ENaC) is hyper-active in CF patients and plays an important role in the pathogenesis of CF. In this study our goal was to determine if antisense oligonucleotides (ASOs) which lowers ENaC levels would potentially reduce CF lung symptoms in mouse models.. Why is this important?. Even with improved care and new therapies available, there remains a portion of the CF population which would benefit from newly discovered drugs. Much effort over the years has tried to identify therapies that rehydrate CF airways by targeting ENaC with the goal of improving disease. This protein is composed of three subunits (α, β, and γ), all of which are required for maximum channel activity. Previously we demonstrated that ASOs specifically targeting ...

BOSTON and DURHAM, NC - Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Parion Sciences today announced that the companies will collaborate to develop investigational epithelial sodium channel (ENaC) inhibitors for the potential treatment of cystic fibrosis (CF) and other pulmonary diseases. Under the agreement, Vertex gains worldwide development and commercial rights to Parions investigational ENaC inhibitors, including P-1037 and P-1055, for CF and other pulmonary diseases. P-1037 is currently being evaluated in an exploratory Phase 2a study in people with CF, regardless of genotype, and Vertex and Parion plan to begin an additional Phase 2a study that adds P-1037 to treatment with the investigational combination of lumacaftor and ivacaftor for people with CF who have two copies of the F508del mutation. Parion will receive an $80 million up-front payment from Vertex with the potential to receive additional development and regulatory milestone payments and tiered royalties related to ...

Jacquillet, Grégory and Chichger, Havovi and Unwin, Robert J. and Shirley, David G. (2013) Protease stimulation of renal sodium reabsorption in vivo by activation of the collecting duct epithelial sodium channel (ENaC). Nephrology Dialysis Transplantation, 28 (4). pp. 839-845. ISSN 1460-2385 ...

Epithelial Na+ channels historically have been classified according to their kinetics, pharmacology, and single channel conductance (see Palmer, 1992; Smith and Benos, 1991). The molecular identity of these channels was unknown until the cloning of the Na(5) channel (classification of Palmer, 1992) independently by Canessa et al. (1993, 1994), by Lingueglia et al. (1993), and Voilley et al. (1994). This channel is also referred to as the epithelial Na+ channel (ENaC)1 and is characterized by a 5-pS single channel conductance, long open and close times, high amiloride sensitivity (Ki , 100 nM), and high Na+ to K+ selectivity. ENaC is composed of three subunits, α, β, and γ, that are necessary to reconstitute the in vivo single channel properties and maximal amiloride-sensitive currents in Xenopus oocytes (Canessa et al., 1994).. The epithelial Na+ channel shares little molecular homology with other known ion channels (for review see Garty and Palmer, 1997). However, this channel belongs to a ...

Using pharmacological screening of a wide spectrum of ion channel antagonists, we found that low concentrations of amiloride inhibited the spiking of water gustatory receptor neurons in Drosophila. Interestingly, several previous studies also demonstrated the effect of amiloride on the spiking of these receptor neurons in the flesh fly and blowfly (Liscia et al., 1997; Sadakata et al., 2002). Using physiological recordings, behavioral assays, and mutational analyses, we identified PPK28 as the putative amiloride-sensitive receptor for gustatory water reception. Further gain-of-function studies showed that PPK28 is sufficient to confer hypoosmotic activity. These results suggest that PPK28 is a good candidate for the Drosophila gustatory water receptor.. The IC50 of amiloride necessary to inhibit the gustatory water response (∼20 μm) was about two orders of magnitude higher than that observed for mammalian ENaC; however, it was comparable to that used for the Drosophila RPK channel (Adams et ...

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The epithelial sodium channel (short: ENaC, also: amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to Na+ ions and that is assembled as a heterotrimer composed of three homologous subunits α or δ, β, and γ, These subunits are encoded by four genes: SCNN1A, SCNN1B, SCNN1G, and SCNN1D. It is involved primarily in the reabsorption of sodium ions at the collecting ducts of the kidneys nephrons. The apical membranes of many tight epithelia contain sodium channels that are characterized primarily by their high affinity for the diuretic blocker amiloride. These channels mediate the first step of active sodium reabsorption essential for the maintenance of body salt and water homeostasis. In vertebrates, the channels control reabsorption of sodium in kidney, colon, lung and sweat glands; they also play a role in taste perception. ENaC is located in the apical membrane of polarized epithelial cells in particular in the kidney (primarily in the ...

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In experimental nephrotic syndrome, urinary sodium excretion is decreased during the early phase of the disease. The molecular mechanism(s) leading to salt retention has not been completely elucidated. The rate-limiting constituent of collecting duct sodium transport is the epithelial sodium channel (ENaC). We examined the abundance of ENaC subunit mRNAs and proteins in puromycin aminonucleoside (PAN)-induced nephrotic syndrome. The time courses of urinary sodium excretion, plasma aldosterone concentration and proteinuria were studied in male Sprague-Dawley rats treated with a single dose of either PAN or vehicle. The relative amounts of αENaC, βENaC and γENaC mRNAs were determined in kidneys from these rats by real-time quantitative TaqMan PCR, and the amounts of proteins by Western blot. The kinetics of urinary sodium excretion and the appearance of proteinuria were comparable with those reported previously. Sodium retention occurred on days 2, 3 and 6 after PAN injection. A significant ...

Acute lung injury (ALI) leading to acute respiratory distress (ARDS) is a global health concern. ARDS patients have significant pulmonary inflammation leading to flooding of the pulmonary alveoli. This prevents normal gas exchange with consequent hypoxemia, and causes mortality. A thin fluid layer in the alveoli is normal. The maintenance of this thin layer results from fluid movement out of the pulmonary capillaries into the alveolar interstitium driven by vascular hydrostatic pressure and then through alveolar tight junctions. This is then balanced by fluid reabsorption from the alveolar space mediated by transepithelial salt and water transport through alveolar cells. Reabsorption is a two-step process: first, sodium enters via sodium-permeable channels in the apical membranes of alveolar type 1 and 2 cells followed by active extrusion of sodium into the interstitium by the basolateral Na+, K+-ATPase. Anions follow the cationic charge gradient and water follows the salt-induced osmotic

This gene encodes a member of the peptidase S1 or chymotrypsin family of serine proteases. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate via a disulfide bond to form the heterodimeric enzyme. This enzyme is highly expressed in prostate epithelia and is one of several proteolytic enzymes found in seminal fluid. This protease exhibits trypsin-like substrate specificity, cleaving protein substrates at the carboxyl terminus of lysine or arginine residues. The encoded protease partially mediates proteolytic activation of the epithelial sodium channel, a regulator of sodium balance, and may also play a role in epithelial barrier formation. [provided by RefSeq, Feb 2016 ...