Rac1-mediated NADPH oxidase release of O<sub>2</sub><sup>−</sup> regulates epithelial sodium channel activity in the alveolar epithelium

Takemura, Yoshizumi; Goodson, Preston; Bao, Hui; Jain, Lucky; Helms, My N.

doi:10.1152/ajplung.00230.2009

Cited by 47 publications

(41 citation statements)

References 28 publications

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“…Incubating monolayers in TEMPOL (a ROS scavenger) did reduce I sc , a result suggesting that endogenous ROS may stimulate ENaC activity (49,59). However, even in the presence of TEMPOL, O 2 produced its concentration-dependent effects, albeit at a lower absolute level (Fig.…”

Section: Effects Of O 2 and Corticosteroids On Na Transportmentioning

confidence: 85%

Oxygen regulation of the epithelial Na channel in the collecting duct

Husted

Sigmund

et al. 2011

American Journal of Physiology-Renal Physiology

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The PO 2 within the kidney changes dramatically from cortex to medulla. The present experiments examined the effect of changing PO 2 on epithelial Na channel (ENaC)-mediated Na transport in the collecting duct using the mpkCCD-c14 cell line. Decreasing ambient O 2 concentration from 20 to 8% decreased ENaC activity by 40%; increasing O2 content to 40% increased ENaC activity by 50%. The O 2 effect required several hours to develop and was not mimicked by the acid pH that developed in monolayers incubated in low-O2 medium. Corticosteroids increased ENaC activity at each O 2 concentration; there was no interaction. The pathways for O2 and steroid regulation of ENaC are different since O2 did not substantially affect Sgk1, ␣-ENaC, Gilz, or Usp2-45 mRNA levels, genes involved in steroid-mediated ENaC regulation. The regulation of ENaC activity by these levels of O2 appears not to be mediated by changes in hypoxia-inducible factor-1␣ or -2␣ activity or a change in AMP kinase activity. Changes in O2 concentration had minimal effect on ␣-or ␥-ENaC mRNA and protein levels; there were moderate effects on ␤-ENaC levels. However, 40% O2 induced substantially greater total ␤-and ␥-ENaC on the apical surface compared with 8% O2; both subunits demonstrated a greater increase in the mature forms. The ␣-ENaC subunit was difficult to detect on the apical surface, perhaps because our antibodies do not recognize the major mature form. These results identify a mechanism of ENaC regulation that may be important in different regions of the kidney and in responses to changes in dietary NaCl.heat shock protein-70; heme oxygenase; adenosine 5=-monophosphate kinase; hypoxia-inducible factor-1␣; corticosteroids; surface expression THE OXYGEN TENSION OF THE renal parenchyma varies from that approaching the PO 2 of arterial blood near the surface of the kidney to considerably lower values in the midcortex (35). The PO 2 of the inner medulla is substantially below that of almost all normal tissues with values of 10 -15 Torr being routinely measured (4, 35). The relatively low PO 2 in both the cortex and the medulla is the result of a functional countercurrent exchange between arterioles and venules. The lower PO 2 in the medulla is believed to predispose to tubular injury in the setting of acute hemodynamic compromise, but the physiological consequences of the widely varying PO 2 of different regions is poorly understood.The collecting duct traverses the axis of the kidney from cortex to papillary tip and, consequently, is exposed to a wide range of PO 2 . It is well known that the rate of Na absorption by the cortical collecting duct is considerably greater than that by the medullary collecting duct (19,48). The reason for this regional difference in Na transport rate is not clear. Two possibilities have been proposed: hypertonicity and the high concentration of transforming growth factor-␤ within the renal medulla (28). Another possibility is the O 2 tension: low PO 2 in lung epithelial cells reduces epithelial Na channel (ENaC) activity (...

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Section: Effects Of O 2 and Corticosteroids On Na Transportmentioning

confidence: 85%

Oxygen regulation of the epithelial Na channel in the collecting duct

Husted

Sigmund

et al. 2011

American Journal of Physiology-Renal Physiology

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“…The potential underlying mechanisms for the negative effects of peroxynitrite include posttranslational modification of vulnerable tyrosine and/or cysteine residues in the channel, although little direct evidence has been obtained to support this (81). The effects of superoxide are most likely due to modulation of NADPH oxidase, and scavengers/inhibitors of superoxide resulted in an acute decrease in channel P o (379). This finding, which suggests that a tonic level of superoxide may be required for sustained channel activity, correlates with studies demonstrating that sustained hypoxia is associated with decreased expression of the three main ENaC subunits (384).…”

Section: Enac In Non-cf-related Lung Diseasementioning

confidence: 99%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

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The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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“…Shibata et al 8 have established recently that signaling cross-talk between Rac1 and the mineralocorticoid receptor modulates receptor activity and identified Rac1 as a therapeutic target for chronic kidney disease. Silva and Garvin 9 and Takemura et al 10 also recently identified an important role for Rac1 in NaCl-induced superoxide generation in the medullary thick ascending limb 9 and in the alveolar epithelium. 10 Members of the Wiskott-Aldrich syndrome protein (WASP)/WAVE family (N-WASP, WASP, and WAVE1, -2, -3 isoforms) share similar domain structure and activate Arp2/3-mediated actin polymerization, leading to distinct downstream effects.…”

mentioning

confidence: 95%

“…Silva and Garvin 9 and Takemura et al 10 also recently identified an important role for Rac1 in NaCl-induced superoxide generation in the medullary thick ascending limb 9 and in the alveolar epithelium. 10 Members of the Wiskott-Aldrich syndrome protein (WASP)/WAVE family (N-WASP, WASP, and WAVE1, -2, -3 isoforms) share similar domain structure and activate Arp2/3-mediated actin polymerization, leading to distinct downstream effects. N-WASP inducibly binds Arp2/3 in response to Cdc42, whereas WAVE proteins constitutively interact with Arp2/3 and are effectors of Rac1 activity.…”

mentioning

confidence: 95%

Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na ⁺ Channel

Karpushev

Levchenko²,

Ilatovskaya³

et al. 2011

Hypertension

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Abstract-The epithelial Naϩ channel (ENaC) is an essential channel responsible for Na ϩ reabsorption in the aldosterone-sensitive distal nephron. Consequently, ENaC is a major effector impacting systemic blood volume and pressure. We have shown recently that Rac1 increases ENaC activity, whereas Cdc42 fails to change channel activity. Here we tested whether Rac1 signaling plays a physiological role in modulating ENaC in native tissue and polarized epithelial cells. We found that Rac1 inhibitor NSC23766 markedly decreased ENaC activity in freshly isolated collecting ducts. Knockdown of Rac1 in native principal cells decreased ENaC-mediated sodium reabsorption and the number of channels at the apical plasma membrane. Members of the Wiskott-Aldrich syndrome protein (WASP) family play a central role in the control of the actin cytoskeleton. N-WASP functions downstream of Cdc42, whereas WAVEs are effectors of Rac1 activity. N-WASP and all 3 isoforms of WAVE significantly increased ENaC activity when coexpressed in Chinese hamster ovary cells. However, wiskostatin, an inhibitor of N-WASP, had no effect on ENaC activity. Immunoblotting demonstrated the presence of WAVE1 and WAVE2 and absence of N-WASP and WAVE3 in mpkCCD c14 and M-1 principal cells. Immunohistochemistry analysis also revealed localization of WAVE1 and WAVE2 but not N-WASP in the cortical collecting duct of Sprague-Dawley rat kidneys. Moreover, patch clamp analysis revealed that Rac1 and WAVE1/2 are parts of the same signaling pathway with respect to activation of ENaC. Thus, our findings suggest that Rac1 is essential for ENaC activity and regulates the channel via WAVE proteins.

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Rac1-mediated NADPH oxidase release of O₂⁻ regulates epithelial sodium channel activity in the alveolar epithelium

Cited by 47 publications

References 28 publications

Oxygen regulation of the epithelial Na channel in the collecting duct

Oxygen regulation of the epithelial Na channel in the collecting duct

ENaCs and ASICs as therapeutic targets

Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na ⁺ Channel

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Rac1-mediated NADPH oxidase release of O2− regulates epithelial sodium channel activity in the alveolar epithelium

Cited by 47 publications

References 28 publications

Oxygen regulation of the epithelial Na channel in the collecting duct

Oxygen regulation of the epithelial Na channel in the collecting duct

ENaCs and ASICs as therapeutic targets

Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na + Channel

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Product

Resources

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Rac1-mediated NADPH oxidase release of O₂⁻ regulates epithelial sodium channel activity in the alveolar epithelium

Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na ⁺ Channel