ENaC inhibition stimulates Cl<sup>−</sup>secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism

Pech, Vladimir; Thumová, Monika; Kim, Young Hee; Agazatian, Diana; Hummler, Edith; Rossier, Bernard C.; Weinstein, Alan M.; Nanami, Masayoshi; Wall, Susan M.

doi:10.1152/ajprenal.00030.2012

Cited by 27 publications

(56 citation statements)

References 49 publications

(62 reference statements)

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“…In the present study, alveolar Cl − and fluid secretion could be effectively mimicked by both pharmacological inhibition of ENaC and alveolar instillation of an Na + -free solution. A similar precedent for the stimulation of Cl − secretion by ENaC inhibition was recently shown in cortical collecting ducts (35). Effects of alveolar Na + uptake inhibition shared the same mechanistic characteristics that we had established for cardiogenic lung edema, in that alveolar Cl − influx and alveolar fluid secretion depended on CFTR, NKCC, and Na + -K + -ATPase.…”

Section: Discussionsupporting

confidence: 82%

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: Discussionsupporting

confidence: 82%

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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“…The channel activity is either not sufficient to trigger a net flux that can be measured by in vitro microperfusion experiments or is compensated by secretion processes that remain to characterized. Regarding chloride transport, it has to be noted that such a secretion pathway has been partially described; it involves the basolateral transporter NKCC1 localized in the B-type intercalated B cells of the CCD [13] . Finally, significant net fluxes of Na + , Cl -and K + are measured in rat or mouse in vitro perfused CCD when animals are either submitted to a sodium-depleted diet or chronically treated with corticosteroids [9,10] .…”

Section: "Classical" Gpcrs That Activates Sodium Absorption In the DImentioning

confidence: 99%

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

Morla

Edwards

Crambert

2016

WJBC

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The renal handling of Na + balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na + represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e ., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na + excretion and are the target of many different regulatory processes that modulate Na + retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na + absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na + excretion, this review also highlights the complexity of these different pathways, and the connections between them.

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“…Amiloride analogs induce natriuresis and chloriuresis by inhibiting ENaC, which reduces Na ϩ absorption in principal cells of the connecting tubule (CNT) and cortical collecting duct (CCD), where ENaC is expressed (15). Since ENaC does not transport Cl Ϫ , how amiloride analogs reduce Cl Ϫ absorption [transepithelial Cl Ϫ flux (J Cl )] in these segments is unresolved (23,30). In CCDs from aldosterone-treated mice, Cl Ϫ absorption is nearly eliminated with application of an amiloride analog, benzamil, to the luminal fluid (23).…”

Section: Channel (Enac) Reduces CLmentioning

confidence: 99%

“…Since ENaC does not transport Cl Ϫ , how amiloride analogs reduce Cl Ϫ absorption [transepithelial Cl Ϫ flux (J Cl )] in these segments is unresolved (23,30). In CCDs from aldosterone-treated mice, Cl Ϫ absorption is nearly eliminated with application of an amiloride analog, benzamil, to the luminal fluid (23). The mechanism of benzamil-sensitive Cl Ϫ flux is thought to occur through paracellular Cl Ϫ transport driven by the lumen-negative transepithelial voltage (V T ) generated by ENaC (13).…”

Section: Channel (Enac) Reduces CLmentioning

confidence: 99%

“…The mechanism of benzamil-sensitive Cl Ϫ flux is thought to occur through paracellular Cl Ϫ transport driven by the lumen-negative transepithelial voltage (V T ) generated by ENaC (13). Our laboratory has shown, however, that benzamil-sensitive Cl Ϫ flux is not strictly coupled to V T (23). For example, the benzamil-sensitive component of J Cl depends on Na…”

Section: Channel (Enac) Reduces CLmentioning

confidence: 99%

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ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl⁻secretion

Nanami

Lazo‐Fernandez

Pech

et al. 2015

American Journal of Physiology-Renal Physiology

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Inhibition of the epithelial Na+ channel (ENaC) reduces Cl− absorption in cortical collecting ducts (CCDs) from aldosterone-treated rats and mice. Since ENaC does not transport Cl−, the purpose of the present study was to explore how ENaC modulates Cl− absorption in mouse CCDs perfused in vitro. Therefore, we measured transepithelial Cl− flux and transepithelial voltage in CCDs perfused in vitro taken from mice that consumed a NaCl-replete diet alone or the diet with aldosterone administered by minipump. We observed that application of an ENaC inhibitor [benzamil (3 μM)] to the luminal fluid unmasks conductive Cl− secretion. During ENaC blockade, this Cl− secretion fell with the application of a nonselective Cl− channel blocker [DIDS (100 μM)] to the perfusate. While single channel recordings of intercalated cell apical membranes in split-open CCDs demonstrated a Cl− channel with properties that resemble the ClC family of Cl− channels, ClC-5 is not the primary pathway for benzamil-sensitive Cl− flux. In conclusion, first, in CCDs from aldosterone-treated mice, most Cl− absorption is benzamil sensitive, and, second, benzamil application stimulates stilbene-sensitive conductive Cl− secretion, which occurs through a ClC-5-independent pathway.

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ENaC inhibition stimulates Cl⁻secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism

Abstract: Pech V, Thumova M, Kim YH, Agazatian D, Hummler E, Rossier BC, Weinstein AM, Nanami M, Wall SM. ENaC inhibition stimulates Cl Ϫ secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism.

Cited by 27 publications

References 49 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

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl⁻secretion

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ENaC inhibition stimulates Cl−secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism

Abstract: Pech V, Thumova M, Kim YH, Agazatian D, Hummler E, Rossier BC, Weinstein AM, Nanami M, Wall SM. ENaC inhibition stimulates Cl Ϫ secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism.

Cited by 27 publications

References 49 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

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl−secretion

Contact Info

Product

Resources

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ENaC inhibition stimulates Cl⁻secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism

ENaC inhibition stimulates HCl secretion in the mouse cortical collecting duct. I. Stilbene-sensitive Cl⁻secretion