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Impaired PTH-induced endocytotic down-regulation of the renal type IIa Na+/Pi-cotransporter in RAP-deficient mice with reduced megalin expression

Bacic, Desa ; Capuano, Paola ; Gisler, Serge ; Pribanic, Sandra ; Christensen, Erik ; Biber, Jürg ; Loffing, Jan ; Kaissling, Brigitte ; Wagner, Carsten ; Murer, Heini

In: Pflügers Archiv, 2003, vol. 446, no. 4, p. 475-484

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    Titre
    • Impaired PTH-induced endocytotic down-regulation of the renal type IIa Na+/Pi-cotransporter in RAP-deficient mice with reduced megalin expression
    Auteur
    • Bacic, Desa. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    • Capuano, Paola. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    • Gisler, Serge. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    • Pribanic, Sandra. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    • Christensen, Erik. Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark
    • Biber, Jürg. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    • Loffing, Jan. Institute of Anatomy, University of Zurich, 8057, Zurich, Switzerland
    • Kaissling, Brigitte. Institute of Anatomy, University of Zurich, 8057, Zurich, Switzerland
    • Wagner, Carsten. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    • Murer, Heini. Institute of Physiology, University of Zurich, 8057, Zurich, Switzerland
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:311923
    Summary
    Inorganic phosphate (Pi) reabsorption in the renal proximal tubule occurs mostly via the Na+/Pi cotransporter type IIa (NaPi-IIa) located in the brush-border membrane (BBM) and is regulated, among other factors, by dietary Pi intake and parathyroid hormone (PTH). The PTH-induced inhibition of Pi reabsorption is mediated by endocytosis of Na/Pi-IIa from the BBM and subsequent lysosomal degradation. Megalin is involved in receptor-mediated endocytosis of proteins from the urine in the renal proximal tubule. The recently identified receptor-associated protein (RAP) is a novel type of chaperone responsible for the intracellular transport of endocytotic receptors such as megalin. Gene disruption of RAP leads to a decrease of megalin in the BBM and to a disturbed proximal tubular endocytotic machinery. Here we investigated whether the distribution of NaPi-IIa and/or its regulation by dietary Pi intake and PTH is affected in the proximal tubules of RAP-deficient mice as a model for megalin loss. In RAP-deficient mice megalin expression was strongly reduced and restricted to a subapical localization. NaPi-IIa protein distribution and abundance in the kidney was not altered. The localization and abundance of the NaPi-IIa interacting proteins MAP17, PDZK-1, D-AKAP2, and NHE-RF1 were also normal. Other transport proteins expressed in the BBM such as the Na+/H+ exchanger NHE-3 and the Na+/sulphate cotransporter NaSi were normally expressed. In whole animals and in isolated fresh kidney slices the PTH-induced internalization of NaPi-IIa was strongly delayed in RAP-deficient mice. PTH receptor expression in the proximal tubule was not affected by the RAP knock-out. cAMP, cGMP or PKC activators induced internalization which was delayed in RAP-deficient mice. In contrast, both wildtype and RAP-deficient mice were able to adapt to high-, normal, and low-Pi diets appropriately as indicated by urinary Pi excretion and NaPi-IIa protein abundance