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Intercalated Cell Depletion and Vacuolar H+-ATPase Mistargeting in an Ae1 R607H Knockin Model.

  • Mumtaz R Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
  • Trepiccione F Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris Descartes University, Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France.
  • Hennings JC Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
  • Huebner AK Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
  • Serbin B Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris Descartes University, Department of Physiology, Hôpital Européen Georges Pompidou, Paris, France.
  • Picard N Centre National de la Recherche Scientifique, Équipe de Recherche Labellisée 8228, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Paris, France.
  • Ullah AKMS Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
  • Păunescu TG Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and.
  • Capen DE Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and.
  • Lashhab RM Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
  • Mouro-Chanteloup I Institut National de la Transfusion Sanguine, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1134, Laboratory of Excellence Globule Rouge-Excellence, Paris Diderot University, Paris, France.
  • Alper SL Nephrology Division and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • Wagner CA Institute of Physiology, University of Zurich, Zurich, Switzerland; and.
  • Cordat E Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
  • Brown D Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and.
  • Eladari D Service de Physiologie Explorations Fonctionnelles Rénales, Centre Hospitalier Universitaire de la Réunion, Hôpital Felix Guyon; and dominique.eladari@inserm.fr christian.huebner@med.uni-jena.de.
  • Hübner CA Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany; dominique.eladari@inserm.fr christian.huebner@med.uni-jena.de.
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  • 2016-12-10
Published in:
  • Journal of the American Society of Nephrology : JASN. - 2017
Cell & Transport Physiology
chronic metabolic acidosis
distal tubule
genetic renal disease
ion transport
transgenic mouse
Acidosis, Renal Tubular
Animals
Anion Exchange Protein 1, Erythrocyte
Kidney Tubules, Collecting
Male
Mice
Models, Biological
Vacuolar Proton-Translocating ATPases
English Distal nephron acid secretion is mediated by highly specialized type A intercalated cells (A-ICs), which contain vacuolar H+-ATPase (V-type ATPase)-rich vesicles that fuse with the apical plasma membrane on demand. Intracellular bicarbonate generated by luminal H+ secretion is removed by the basolateral anion-exchanger AE1. Chronically reduced renal acid excretion in distal renal tubular acidosis (dRTA) may lead to nephrocalcinosis and renal failure. Studies in MDCK monolayers led to the proposal of a dominant-negative trafficking mechanism to explain AE1-associated dominant dRTA. To test this hypothesis in vivo, we generated an Ae1 R607H knockin mouse, which corresponds to the most common dominant dRTA mutation in human AE1, R589H. Compared with wild-type mice, heterozygous and homozygous R607H knockin mice displayed incomplete dRTA characterized by compensatory upregulation of the Na+/HCO3- cotransporter NBCn1. Red blood cell Ae1-mediated anion-exchange activity and surface polypeptide expression did not change. Mutant mice expressed far less Ae1 in A-ICs, but basolateral targeting of the mutant protein was preserved. Notably, mutant mice also exhibited reduced expression of V-type ATPase and compromised targeting of this proton pump to the plasma membrane upon acid challenge. Accumulation of p62- and ubiquitin-positive material in A-ICs of knockin mice suggested a defect in the degradative pathway, which may explain the observed loss of A-ICs. R607H knockin did not affect type B intercalated cells. We propose that reduced basolateral anion-exchange activity in A-ICs inhibits trafficking and regulation of V-type ATPase, compromising luminal H+ secretion and possibly lysosomal acidification.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/11508
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