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Original Articles

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

Alexey V. Karpushev, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov, Alexander Staruschenko
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https://doi.org/10.1161/HYPERTENSIONAHA.110.157784
Hypertension. 2011;HYPERTENSIONAHA.110.157784
Originally published April 4, 2011
Alexey V. Karpushev
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Vladislav Levchenko
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Daria V. Ilatovskaya
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Tengis S. Pavlov
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Alexander Staruschenko
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Abstract

The epithelial Na+ channel (ENaC) is an essential channel responsible for Na+ 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 mpkCCDc14 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.

  • aldosterone
  • aldosterone-sensitive distal nephron
  • epithelial transport
  • Wiskott-Aldrich syndrome protein
  • actin cytoskeleton
  • Received June 11, 2010.
  • Revision received June 30, 2010.
  • Accepted March 14, 2011.
  • © 2011 American Heart Association, Inc.
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    Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na+ Channel
    Alexey V. Karpushev, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov and Alexander Staruschenko
    Hypertension. 2011;HYPERTENSIONAHA.110.157784, originally published April 4, 2011
    https://doi.org/10.1161/HYPERTENSIONAHA.110.157784

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    Novel Role of Rac1/WAVE Signaling Mechanism in Regulation of the Epithelial Na+ Channel
    Alexey V. Karpushev, Vladislav Levchenko, Daria V. Ilatovskaya, Tengis S. Pavlov and Alexander Staruschenko
    Hypertension. 2011;HYPERTENSIONAHA.110.157784, originally published April 4, 2011
    https://doi.org/10.1161/HYPERTENSIONAHA.110.157784
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