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The Role of Intercalated Cell Nedd4-2 in BP Regulation, Ion Transport, and Transporter Expression.

  • Nanami, Masayoshi1
  • Pham, Truyen D1
  • Kim, Young Hee1
  • Yang, Baoli2
  • Sutliff, Roy L3
  • Staub, Olivier4, 5
  • Klein, Janet D1
  • Lopez-Cayuqueo, Karen I6, 7
  • Chambrey, Regine8
  • Park, Annie Y1
  • Wang, Xiaonan1
  • Pech, Vladimir1
  • Verlander, Jill W9
  • Wall, Susan M10, 11
  • 1 Renal and.
  • 2 Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa.
  • 3 Pulmonary Divisions, Department of Medicine and.
  • 4 Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland. , (Switzerland)
  • 5 National Centre of Competence in Research "," Zurich, Switzerland. , (Switzerland)
  • 6 Centro de Estudios Cientificos, Valdivia, Chile. , (Chile)
  • 7 Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Université Paris-Descartes, Paris, France. , (France)
  • 8 Institut National de la Santé et de la Recherche Médicale U1188, Universite de la Reunion, Plateforme Cyclotron Réunion Océan Indien, St. Denis, Ile de la Reunion, France; and. , (France)
  • 9 Renal Division, Department of Medicine, University of Florida at Gainesville, Gainesville, Florida.
  • 10 Renal and [email protected]
  • 11 Department of Physiology, Emory University School of Medicine, Atlanta, Georgia. , (Georgia)
Published Article
Journal of the American Society of Nephrology
American Society of Nephrology
Publication Date
Jun 01, 2018
DOI: 10.1681/ASN.2017080826
PMID: 29773687


BackgroundNedd4-2 is an E3 ubiquitin-protein ligase that associates with transport proteins, causing their ubiquitylation, and then internalization and degradation. Previous research has suggested a correlation between Nedd4-2 and BP. In this study, we explored the effect of intercalated cell (IC) Nedd4-2 gene ablation on IC transporter abundance and function and on BP.Methods We generated IC Nedd4-2 knockout mice using Cre-lox technology and produced global pendrin/Nedd4-2 null mice by breeding global Nedd4-2 null (Nedd4-2-/- ) mice with global pendrin null (Slc26a4-/- ) mice. Mice ate a diet with 1%-4% NaCl; BP was measured by tail cuff and radiotelemetry. We measured transepithelial transport of Cl- and total CO2 and transepithelial voltage in cortical collecting ducts perfused in vitro Transporter abundance was detected with immunoblots, immunohistochemistry, and immunogold cytochemistry.Results IC Nedd4-2 gene ablation markedly increased electroneutral Cl-/HCO3- exchange in the cortical collecting duct, although benzamil-, thiazide-, and bafilomycin-sensitive ion flux changed very little. IC Nedd4-2 gene ablation did not increase the abundance of type B IC transporters, such as AE4 (Slc4a9), H+-ATPase, barttin, or the Na+-dependent Cl-/HCO3- exchanger (Slc4a8). However, IC Nedd4-2 gene ablation increased CIC-5 total protein abundance, apical plasma membrane pendrin abundance, and the ratio of pendrin expression on the apical membrane to the cytoplasm. IC Nedd4-2 gene ablation increased BP by approximately 10 mm Hg. Moreover, pendrin gene ablation eliminated the increase in BP observed in global Nedd4-2 knockout mice.Conclusions IC Nedd4-2 regulates Cl-/HCO3- exchange in ICs., Nedd4-2 gene ablation increases BP in part through its action in these cells.

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