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Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel–Mediated Sodium Transport in Collecting Duct Principal Cells

Eva Dizin, Valérie Olivier, Isabelle Roth, Ali Sassi, Grégoire Arnoux, Suresh Ramakrishnan, Sandrine Morel, Brenda R. Kwak, Johannes Loffing, Edith Hummler, Roland H. Wenger, Ian J. Frew and Eric Feraille
JASN December 2021, 32 (12) 3130-3145; DOI: https://doi.org/10.1681/ASN.2021010046
Eva Dizin
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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Valérie Olivier
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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  • ORCID record for Valérie Olivier
Isabelle Roth
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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Ali Sassi
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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Grégoire Arnoux
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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Suresh Ramakrishnan
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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Sandrine Morel
3Department of Pathology and Immunology, University of Geneva, CMU, Geneva, Switzerland
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Brenda R. Kwak
3Department of Pathology and Immunology, University of Geneva, CMU, Geneva, Switzerland
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Johannes Loffing
2National Centre of Competence in Research “Kidney.CH”, Switzerland
4Institute of Anatomy, University of Zürich, Zürich, Switzerland
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Edith Hummler
2National Centre of Competence in Research “Kidney.CH”, Switzerland
5Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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Roland H. Wenger
2National Centre of Competence in Research “Kidney.CH”, Switzerland
6Institute of Physiology, University of Zürich, Zürich, Switzerland
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Ian J. Frew
7Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, Medical Centre - University of Freiburg, Freiburg, Germany
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Eric Feraille
1Department of Cellular Physiology and Metabolism, University of Geneva, CMU, Geneva, Switzerland
2National Centre of Competence in Research “Kidney.CH”, Switzerland
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Significance Statement

The hypoxia-inducible factor (HIF) pathway is a key mediator of cellular adaptation to low oxygen tension. The aldosterone-sensitive distal nephron is the site of active and highly ATP-consuming sodium reabsorption, according to the requirement of sodium balance. The authors found that activation of the HIF pathway in cultured principal cells led to decreased amiloride-sensitive current (reflecting decreased epithelial sodium channel [ENaC] activity) and decreased expression of ENaC subunits, whereas HIF silencing led to increased amiloride-sensitive current and expression of ENaC subunits. Hypoxic control mice displayed decreased γENaC, whereas HIF1α knockout mice displayed increased γENaC. These findings suggest that the HIF pathway controls ENaC expression and activity, and may represent a negative feedback mechanism to prevent hypoxia and/or reactive oxygen species–induced cell damage under sustained stimulation of sodium transport.

Abstract

Background Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxia-inducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)–dependent sodium transport.

Methods We investigated HIF’s effect on ENaC expression in mpkCCDcl4 cells (a model of collecting duct principal cells) using real-time PCR and western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule–specific Hif1α knockout mice.

Results In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of βENaC and γENaC, as well as of Na,K-ATPase. HIF1α silencing increased βENaC and γENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γENaC abundance under high sodium intake.

Conclusions This study reveals that γENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.

  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (12)
Journal of the American Society of Nephrology
Vol. 32, Issue 12
December 2021
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Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel–Mediated Sodium Transport in Collecting Duct Principal Cells
Eva Dizin, Valérie Olivier, Isabelle Roth, Ali Sassi, Grégoire Arnoux, Suresh Ramakrishnan, Sandrine Morel, Brenda R. Kwak, Johannes Loffing, Edith Hummler, Roland H. Wenger, Ian J. Frew, Eric Feraille
JASN Dec 2021, 32 (12) 3130-3145; DOI: 10.1681/ASN.2021010046

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Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel–Mediated Sodium Transport in Collecting Duct Principal Cells
Eva Dizin, Valérie Olivier, Isabelle Roth, Ali Sassi, Grégoire Arnoux, Suresh Ramakrishnan, Sandrine Morel, Brenda R. Kwak, Johannes Loffing, Edith Hummler, Roland H. Wenger, Ian J. Frew, Eric Feraille
JASN Dec 2021, 32 (12) 3130-3145; DOI: 10.1681/ASN.2021010046
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