A mouse model for distal renal tubular acidosis reveals a previously unrecognized role of the V-ATPase a4 subunit in the proximal tubule

Authors

  • J. Christopher Hennings,

    1. Institut für Humangenetik, Universitätsklinikum Jena, Jena, Germany
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    • These authors contributed equally to this work.

  • Nicolas Picard,

    1. Faculté de Médecine, Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France
    2. INSERM UMRS 872, Centre de Recherche des Cordeliers, Paris, France
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    • These authors contributed equally to this work.

  • Antje K. Huebner,

    1. Institut für Humangenetik, Universitätsklinikum Jena, Jena, Germany
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    • These authors contributed equally to this work.

  • Tobias Stauber,

    1. Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany
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  • Hannes Maier,

    1. Institut für Audioneurotechnologie und Abteilung für Experimentelle Ohrenheilkunde der Klinik für Hals-Nasen-Ohrenheilkunde, Medizinische Hochschule Hannover, Hannover, Germany
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  • Dennis Brown,

    1. Program in Membrane Biology, Division of Nephrology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Simches Research Center, Boston, USA
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  • Thomas J. Jentsch,

    1. Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany
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  • Rosa Vargas-Poussou,

    1. Hopital Européen Georges Pompidou, Service de Génétique, Assistance Publique-Hopitaux de Paris, Paris, France
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  • Dominique Eladari,

    Corresponding author
    1. Faculté de Médecine, Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France
    2. INSERM UMRS 872, Centre de Recherche des Cordeliers, Paris, France
    3. Département de Physiologie, Hopital Européen Georges Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France
    • Dominique Eladari, Tel: +33 1 55 42 78 63; Fax: +33 1 46 33 41 72

      Christian A. Hübner, Tel: +493641 935500; Fax: +493641 935502

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  • Christian A. Hübner

    Corresponding author
    1. Institut für Humangenetik, Universitätsklinikum Jena, Jena, Germany
    • Dominique Eladari, Tel: +33 1 55 42 78 63; Fax: +33 1 46 33 41 72

      Christian A. Hübner, Tel: +493641 935500; Fax: +493641 935502

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Abstract

The V-ATPase is a multisubunit complex that transports protons across membranes. Mutations of its B1 or a4 subunit are associated with distal renal tubular acidosis and deafness. In the kidney, the a4 subunit is expressed in intercalated cells of the distal nephron, where the V-ATPase controls acid/base secretion, and in proximal tubule cells, where its role is less clear. Here, we report that a4 KO mice suffer not only from severe acidosis but also from proximal tubule dysfunction with defective endocytic trafficking, proteinuria, phosphaturia and accumulation of lysosomal material and we provide evidence that these findings may be also relevant in patients. In the inner ear, the a4 subunit co-localized with pendrin at the apical side of epithelial cells lining the endolymphatic sac. As a4 KO mice were profoundly deaf and displayed enlarged endolymphatic fluid compartments mirroring the alterations in pendrin KO mice, we propose that pendrin and the proton pump co-operate in endolymph homeostasis. Thus, our mouse model gives new insights into the divergent functions of the V-ATPase and the pathophysiology of a4-related symptoms.

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