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Author Notes:


S.M.W. and J.L. wrote the main manuscript text. C.C., Y.H.K, V.P., D.C.A., T.D.P., and D.L.-C. did the experiments. D.L-C., D.C.A., and S.M.W. prepared the figures. All authors reviewed the manuscript.

The technical support of Monique Carrel is kindly acknowledged. The authors thank Carsten Wagner (University of Zurich), Dennis Brown (Massachusetts General Hospital, Harvard Medical School), and Steven Gluck (University of California San Francisco) for providing the rabbit, anti-mouse pendrin, the chicken anti-H+-ATPase E subunit, and the mouse, anti-bovine H+-ATPase antibodies, respectively. We thank Drs. Bernard Rossier and Edith Hummler for providing the Liddle’s and the collecting duct-specific αENaC knockout mice.

S.M.W. owns stock in Johnson & Johnson, Merck & Co., Abbott Laboratories, Thermo Fisher Scientific, Becton Dickinson & Co., and Danaher. All other authors declare no competing interests.

Johannes Loffing and Vladimir Pech contributed equally to this work.


Research Funding:

Open access funding provided by University of Zurich. SMW is supported by DK 119793. JL is supported by the Swiss National Centre of Competence in Research “NCCR Kidney.CH” and a project grant from the Swiss National Science Foundation (310030_173276/1).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Physiology
  • Pendrin
  • ENaC
  • Aldosterone
  • Intercalated cells
  • RAT

Pendrin abundance, subcellular distribution, and function are unaffected by either alpha ENaC gene ablation or by increasing ENaC channel activity


Journal Title:



Volume 475, Number 5


, Pages 607-620

Type of Work:

Article | Final Publisher PDF


The intercalated cell Cl−/HCO3− exchanger, pendrin, modulates ENaC subunit abundance and function. Whether ENaC modulates pendrin abundance and function is however unknown. Because αENaC mRNA has been detected in pendrin-positive intercalated cells, we hypothesized that ENaC, or more specifically the αENaC subunit, modulates intercalated cell function. The purpose of this study was therefore to determine if αENaC is expressed at the protein level in pendrin-positive intercalated cells and to determine if αENaC gene ablation or constitutively upregulating ENaC activity changes pendrin abundance, subcellular distribution, and/or function. We observed diffuse, cytoplasmic αENaC label in pendrin-positive intercalated cells from both mice and rats, with much lower label intensity in pendrin-negative, type A intercalated cells. However, while αENaC gene ablation within principal and intercalated cells of the CCD reduced Cl− absorption, it did not change pendrin abundance or subcellular distribution in aldosterone-treated mice. Further experiments used a mouse model of Liddle’s syndrome to explore the effect of increasing ENaC channel activity on pendrin abundance and function. The Liddle’s variant did not increase either total or apical plasma membrane pendrin abundance in aldosterone-treated or in NaCl-restricted mice. Similarly, while the Liddle’s mutation increased total Cl− absorption in CCDs from aldosterone-treated mice, it did not significantly affect the change in Cl− absorption seen with pendrin gene ablation. We conclude that in rats and mice, αENaC localizes to pendrin-positive ICs where its physiological role remains to be determined. While pendrin modulates ENaC abundance, subcellular distribution, and function, ENaC does not have a similar effect on pendrin.

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© The Author(s) 2023

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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