H2O2 Regulates Lung Epithelial Sodium Channel (ENaC) via Ubiquitin-like Protein Nedd8

Downs, Charles A.; Kumar, Amrita; Kreiner, Lisa; Johnson, Nicholle M.; Helms, My N.

doi:10.1074/jbc.m112.389536

Cited by 39 publications

(39 citation statements)

References 42 publications

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“…1). Our studies show that the 65-kD mature and the cleaved form of a-ENaC, which plays a role in HSC-and NSC-mediated changes in transport capacity, was indeed increased after acute CSE exposure (18). Based on this new observation of HSC and NSC activation by CSE exposure, we expect the acute effects of cigarette smoke-induced lung injury to be more severe than, for example, acute LPS-mediate injury because of differences in channel-mediated responses.…”

Section: Single-channel Analysis Of the Effect Of Cse On Ion Transportmentioning

confidence: 59%

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Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

Downs

Kreiner²,

Trac³

et al. 2013

Am J Respir Cell Mol Biol

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Cigarette smoke contains high levels of reactive species. Moreover, cigarette smoke can induce cellular production of oxidants. The purpose of this study was to determine the effect of cigarette smoke extract (CSE)-derived oxidants on epithelial sodium channel (ENaC) activity in alveolar type 1 (T1) and type 2 (T2) cells and to measure corresponding rates of fluid clearance in mice receiving a tracheal instillation of CSE. Single-channel patch clamp analysis of T1 and T2 cells demonstrate that CSE exposure increases ENaC activity (NPo), measured as the product of the number of channels (N) and a channels open probability (Po), from 0.17 6 0.07 to 0.34 6 0.10 (n ¼ 9; P ¼ 0.04) in T1 cells. In T2 cells, CSE increased NPo from 0.08 6 0.03 to 0.35 6 0.10 (n ¼ 9; P ¼ 0.02). In both cell types, addition of tetramethylpiperidine and glutathione attenuated CSE-induced increases in ENaC NPo. Biotinylation and cycloheximide chase assays indicate that CSE-derived ROS increases channel activity, in part, by maintaining cell surface expression of the a-ENaC subunit. In vivo studies show that tracheal instillation of CSE promoted alveolar fluid clearance after 105 minutes compared with vehicle control (n ¼ 10/ group; P , 0.05).

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Section: Single-channel Analysis Of the Effect Of Cse On Ion Transportmentioning

confidence: 59%

“…Previously, we have shown that ENaC is regulated by free radicals, such as superoxide (15) and H 2 O 2 (2,8,16,(17)(18)(19). Therefore, we tested the hypothesis that cigarette smoke extract (CSE) exposure would increase ENaC activity in lung T1 and T2 cells via oxidant signaling.…”

mentioning

confidence: 99%

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

Downs

Kreiner²,

Trac³

et al. 2013

Am J Respir Cell Mol Biol

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“…It was also found that mRNA and protein expression of ENaC subunits was significantly increased in the renal cortex of the SS rats fed a high-salt diet (87,152). Since it was previously reported that ROS might be involved in the control of ENaC (47,81,190), these pathways may together act to amplify the development of salt-sensitive hypertension in SS rats. Further studies will be required to link ROS production with these tubular events in the cortex of SS rats.…”

Section: Medullary O 2 ·ϫ No and H 2 O 2 As Determinants Of Blood mentioning

confidence: 91%

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Cowley

Abe

Mori

et al. 2015

American Journal of Physiology-Renal Physiology

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logical evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na ϩ reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.superoxide (O 2 ·Ϫ ); hydrogen peroxide (H2O2); nitric oxide (NO); NAD(P)H oxidase; mTAL; medullary blood flow; kidney; Dahl SS rats REACTIVE OXYGEN SPECIES (ROS) are chemically reactive molecules derived from oxygen, whose role as mediators of intracellular signaling cascades is well recognized. The following is a brief review of physiological data linking superoxide (O 2 ·Ϫ ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO) production in the medullary thick ascending limbs of Henle (mTAL) to sodium (Na ϩ ) homeostasis, the regulation of medullary blood flow (MBF), and the long-term regulation of arterial blood pressure. MBF to the renal medulla can be importantly controlled by the constriction and dilation of the descending vasa recta (VR) capillaries, which branch from the efferent arterioles of the juxtamedullary glomeruli (49, 147, 149) and whose tone is controlled by the smooth muscle-like pericytes (49, 90, 146 -149). The role of NO cross talk from mTAL to surrounding VR in the renal medulla has been reviewed in detail elsewhere (19, 33) and will be discussed here largely with regard to its ROS-related counterregulatory functions. The present review will first summarize data showing that either the excess endogenous production or reduced scavenging of O 2 ·Ϫ or H 2 O 2 within the renal medulla results in a decrease in MBF and Na ϩ excretion, leading to hypertension and renal injury. Second, evidence will be summarized supporting the hypothesis that a high dietary salt intake results in increased luminal flow and delivery of NaCl to the mTAL, thereby signaling via both mechanical forces (stretch and shear) and increased Na ϩ transport, an increased mitochondrial and membrane NA-D(P)H oxidase production of O 2 ·Ϫ and H 2 O 2 . Third, studies will be reviewed showing that reduction of MBF leads to hypertension a...

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“…We have previously reported the effects of a variety of agonists on the biophysical properties of ENaC-in particular, the number of inserted channels and the molecular characteristics of these channels (19,28,29,37,38). ENaC channels are classified based on their selectivity for Na Figures 3D and 4C).…”

Section: Effect Of Hages On Biophysical Properties Of Enacmentioning

confidence: 99%

Receptor for Advanced Glycation End-Products Regulates Lung Fluid Balance via Protein Kinase C–gp91^phox Signaling to Epithelial Sodium Channels

Downs

Kreiner

Johnson

et al. 2015

Am J Respir Cell Mol Biol

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The receptor for advanced glycation end-products (RAGE), a multiligand member of the Ig family, may play a crucial role in the regulation of lung fluid balance. We quantified soluble RAGE (sRAGE), a decoy isoform, and advanced glycation end-products (AGEs) from the bronchoalveolar lavage fluid of smokers and nonsmokers, and tested the hypothesis that AGEs regulate lung fluid balance through protein kinase C (PKC)-gp91 phox signaling to the epithelial sodium channel (ENaC). Human bronchoalveolar lavage samples from smokers showed increased AGEs (9.02 6 3.03 mg versus 2.48 6 0.53 mg), lower sRAGE (1,205 6 292 pg/ml versus 1,910 6 263 pg/ml), and lower volume(s) of epithelial lining fluid (97 6 14 ml versus 133 6 17 ml). sRAGE levels did not predict ELF volumes in nonsmokers; however, in smokers, higher volumes of ELF were predicted with higher levels of sRAGE. Single-channel patch clamp analysis of rat alveolar epithelial type 1 cells showed that AGEs increased ENaC activity measured as the product of the number of channels (N) and the open probability (Po) (NPo) from 0.19 6 0.08 to 0.83 6 0.22 (P = 0.017) and the subsequent addition of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl decreased ENaC NPo to 0.15 6 0.07 (P = 0.01). In type 2 cells, human AGEs increased ENaC NPo from 0.12 6 0.05 to 0.53 6 0.16 (P = 0.025) and the addition of 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-N-oxyl decreased ENaC NPo to 0.10 6 0.03 (P = 0.013). Using molecular and biochemical techniques, we observed that inhibition of RAGE and PKC activity attenuated AGE-induced activation of ENaC. AGEs induced phosphorylation of p47 phox and increased gp91 phox -dependent reactive oxygen species production, a response that was abrogated with RAGE or PKC inhibition. Finally, tracheal instillation of AGEs promoted clearance of lung fluid, whereas concomitant inhibition of RAGE, PKC, and gp91 phox abrogated the response.Keywords: acute respiratory distress syndrome; chronic obstructive pulmonary disease; pulmonary edema; alveolar microenvironment; lung injury Clinical RelevanceReceptor for advanced glycation end-products (RAGE) plays a critical role in regulating inflammation in the lung and may be a therapeutic target in the treatment of acute and chronic lung diseases. Herein we describe the signal transduction pathway through which RAGE regulates the epithelial sodium channel.

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H2O2 Regulates Lung Epithelial Sodium Channel (ENaC) via Ubiquitin-like Protein Nedd8

Cited by 39 publications

References 42 publications

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Receptor for Advanced Glycation End-Products Regulates Lung Fluid Balance via Protein Kinase C–gp91^phox Signaling to Epithelial Sodium Channels

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H2O2 Regulates Lung Epithelial Sodium Channel (ENaC) via Ubiquitin-like Protein Nedd8

Cited by 39 publications

References 42 publications

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Receptor for Advanced Glycation End-Products Regulates Lung Fluid Balance via Protein Kinase C–gp91phox Signaling to Epithelial Sodium Channels

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Resources

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Receptor for Advanced Glycation End-Products Regulates Lung Fluid Balance via Protein Kinase C–gp91^phox Signaling to Epithelial Sodium Channels