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2 results on '"Huebner, Antje K"'

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

Author

Francesco Trepiccione, Seth L. Alper, Nicolas Picard, Emmanuelle Cordat, A.K.M. Shahid Ullah, Bettina Serbin, J. Christopher Hennings, Teodor G. Păunescu, Diane E. Capen, Dominique Eladari, Rizwan Mumtaz, Dennis Brown, Christian A. Hübner, Isabelle Mouro-Chanteloup, Rawad Lashhab, Carsten A. Wagner, Antje K. Huebner, Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Cardio-Thoracic and Respiratory Science, Second University of Naples, Naples, Italy, Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Physiology, University of Alberta, Edmonton, Alberta, Canada, Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Institut National de la Transfusion Sanguine [Paris] (INTS), Nephrology Division and Vascular Biology Research Center, Beth Israel DeaconessMedical Center, Department of Medicine, HarvardMedical School, Boston,Massachusetts, Institute of Physiology, University of Zurich, Zurich, Switzerland, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Picard, Nicolas, University of Alberta, Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Zurich, Eladari, Dominique, Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Physiologie Explorations Fonctionnelles Rénales, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Mumtaz, Rizwan, Trepiccione, Francesco, Hennings, J. Christopher, Huebner, Antje K, Serbin, Bettina, Picard, Nicola, Ullah, A. K. M. Shahid, Păunescu, Teodor G, Capen, Diane E, Lashhab, Rawad M, Mouro Chanteloup, Isabelle, Alper, Seth L, Wagner, Carsten A, Cordat, Emmanuelle, Brown, Denni, Hübner, Christian A., Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and ††Nephrology Division and Vascular Biology Research Center, Beth Israel DeaconessMedical Center, Department of Medicine, HarvardMedical School, Boston,Massachusetts, 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, Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Diabète athérothrombose et thérapies Réunion Océan Indien ( DéTROI ), Université de la Réunion ( UR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, distal tubule, Vacuolar Proton-Translocating ATPases, chronic metabolic acidosis, ATPase, [SDV]Life Sciences [q-bio], Mutant, 030232 urology & nephrology, 610 Medicine & health, Biology, Models, Biological, 10052 Institute of Physiology, Cell & Transport Physiology, ion transport, Mice, 03 medical and health sciences, 0302 clinical medicine, Distal renal tubular acidosis, Mutant protein, Anion Exchange Protein 1, Erythrocyte, medicine, Secretion, Intercalated Cell, Kidney Tubules, Collecting, 2727 Nephrology, [ SDV ] Life Sciences [q-bio], chronic metabolic acidosi, Animal, genetic renal disease, Acidosis, Renal Tubular, General Medicine, medicine.disease, Cell biology, [SDV] Life Sciences [q-bio], transgenic mouse, 030104 developmental biology, Biochemistry, Nephrology, biology.protein, 570 Life sciences, biology, Cotransporter, Intracellular
Abstract

International audience; 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. Intra-cellular 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 + /HCO 3 2 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.

Published
2017

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