Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease

Azad, Abul Kalam; Rauh, R. D.; Vermeulen, François; Jaspers, Martine; Korbmacher, Judit; Boissier, Brigitte; Bassinet, L.; Fichou, Yann; Georges, Marie des; Stanke, Frauke; Boeck, K. De; Dupont, Lieven; Balaščaková, Miroslava; Hjelte, Lena; Lebecque, Patrick; Radojković, Dragica; Castellani, Carlo; Schwartz, Marianne; Stuhrmann, Manfred; Schwarz, Martin; Skalická, Veronika; Monestrol, Isabelle de; Girodon, Emmanuelle; Férec, Claude; Claustres, Mireille; Tümmler, Burkhard; Cassiman, Jean‐Jacques; Korbmacher, Christoph; Cuppens, Harry

doi:10.1002/humu.21011

Cited by 79 publications

(83 citation statements)

References 39 publications

(47 reference statements)

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“…Although it has become wildly recognized that CFTR negatively regulates ENaC function and expression (28), ENaC may also impact on Cl − flux through CFTR. Airwayspecific overexpression of ENaC produces a cystic fibrosis-like phenotype in mice (29), and mutations in amiloride-sensitive epithelial sodium channels are associated with a cystic fibrosis-like disease in patients (30), suggesting that CFTR secretory activity may be inversely regulated by Na + absorption by ENaC. Hence, we considered that the reversal of transepithelial Cl − flux may have been caused by an inhibition of ENaC activity in the presence of an active Na + -K + -ATPase.…”

Section: Discussionmentioning

confidence: 99%

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Solymosi

Kaestle-Gembardt

Vadász

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Alveolar fluid clearance driven by active epithelial Na + and secondary Cl − absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na + channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl − secretion and alveolar Cl − influx were quantified by radionuclide tracing and alveolar Cl − imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl − secretion and alveolar Cl − influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na + -K + -Cl − cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR −/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl − secretion that were again CFTR-, NKCC-, and Na + -K + -ATPase-dependent. Our findings show a reversal of transepithelial Cl − and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl − and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.epithelial Cl − transport | pulmonary edema T raditionally, the formation of cardiogenic pulmonary edema has been attributed to passive fluid filtration across an intact alveolocapillary barrier along an increased hydrostatic pressure gradient. However, recent studies show that cardiogenic edema is critically regulated by active signaling processes. Activation of mechanosensitive endothelial ion channels increases lung vascular permeability (1), whereas alveolar epithelial cells lose their physiological ability to clear the distal airspaces from excess fluid by their capacity to actively transport ions across the epithelial barrier (2-4).In the intact lung, the predominant force driving alveolar fluid clearance is an active transepithelial Na + transport from the alveolar into the interstitial space. A major portion of the apical Na + entry is mediated by the amiloride-inhibitable epithelial Na + channel (ENaC), with basolateral Na + extrusion through the Na + -K + -ATPase (5). Cl − and water are considered to follow paracellularly for electroneutrality and osmotic balance. In cardiogenic lung edema, the physiological protection against alveolar flooding provided by an intact alveolar fluid clearance is largely attenuated (3, 4). Previously, ...

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Section: Discussionmentioning

confidence: 99%

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Solymosi

Kaestle-Gembardt

Vadász

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, individuals who are heterozygous for the ⌬F508 mutation in CFTR (cystic fibrosis transmembrane conductance regulator) lack overt pulmonary symptoms. Mutations in ENaC have been reported in individuals with atypical cystic fibrosis who are heterozygous for the ⌬F508 CFTR mutation (49,50). For example, an activating ENaC mutation (␣W493R) that has loss of Na ϩ self-inhibition has been described in this population (39,49).…”

Section: Enac Gain-of-function Polymorphisms and Mutationsmentioning

confidence: 99%

“…Mutations in ENaC have been reported in individuals with atypical cystic fibrosis who are heterozygous for the ⌬F508 CFTR mutation (49,50). For example, an activating ENaC mutation (␣W493R) that has loss of Na ϩ self-inhibition has been described in this population (39,49). At present, it is unclear whether individuals with atypical cystic fibrosis and activating ENaC mutations have elevated blood pressures.…”

Section: Enac Gain-of-function Polymorphisms and Mutationsmentioning

confidence: 99%

Role of Epithelial Sodium Channels and Their Regulators in Hypertension

Soundararajan

Pearce

Hughey

et al. 2010

Journal of Biological Chemistry

103

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The kidney has a central role in the regulation of blood pressure, in large part through its role in the regulated reabsorption of filtered Na ؉ . Epithelial Na ؉ channels (ENaCs) are expressed in the most distal segments of the nephron and are a target of volume regulatory hormones. A variety of factors regulate ENaC activity, including several aldosterone-induced proteins that are present within an ENaC regulatory complex. Proteases also regulate ENaC by cleaving the channel and releasing intrinsic inhibitory tracts. Polymorphisms or mutations within channel subunits or regulatory pathways that enhance channel activity may contribute to an increase in blood pressure in individuals with essential hypertension.

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“…AZAD et al [2] have also investigated the frequency of ENaC mutations in ENaC alpha, beta and gamma genes in a cohort of 76 patients with cystic fibrosis (CF)-like disease and with only one or no mutation in the CFTR gene. They found a significant increase in missense mutations or variants in patients (15.3%) compared with controls (8.9%) [2]. Moreover, a variant in ENaC alpha gene called p.W493R was found at a more than two-fold significantly increased incidence in patients (8%) compared with controls (3%) and, in the Xenopus laevis oocyte expression system, p.W493R was found to result in a more than four-fold higher ENaC activity.…”

Section: To the Editorsmentioning

confidence: 99%

“…We have recently screened ENaC beta and gamma genes in 55 patients with diffuse bronchiectasis and with only one or no CFTR mutation/variant and showed that eight (15%) patients carried at least one missense mutation in these ENaC genes [1]. AZAD et al [2] have also investigated the frequency of ENaC mutations in ENaC alpha, beta and gamma genes in a cohort of 76 patients with cystic fibrosis (CF)-like disease and with only one or no mutation in the CFTR gene. They found a significant increase in missense mutations or variants in patients (15.3%) compared with controls (8.9%) [2].…”

Section: To the Editorsmentioning

confidence: 99%

Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease

Fajac¹,

Viel²,

Gaitch³

et al. 2009

European Respiratory Journal

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Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease

Cited by 79 publications

References 39 publications

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Role of Epithelial Sodium Channels and Their Regulators in Hypertension

Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease

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