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Kidney-Specific Inactivation of the Megalin Gene Impairs Trafficking of Renal Inorganic Sodium Phosphate Cotransporter (NaPi-IIa)

Sebastian Bachmann^*, Uwe Schlichting^*, Beate Geist^*, Kerim Mutig^*, Thomas Petsch^*, Desa Bacic^,, Carsten A. Wagner, Brigitte Kaissling, Jürg Biber, Heini Murer and Thomas E. Willnow

*Department of Anatomy, Charité, University Medical School of Berlin, and Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; and Departments of Physiology and Anatomy, University of Zürich, Switzerland.

Correspondence to: Prof. Dr. Sebastian Bachmann, AG Anatomie der Charité, Campus Mitte, Philippstr. 12, D-10098 Berlin, Germany. Phone: +49-30-450-528-001; Fax: +49-30-450-528-922; E-mail: sbachm{at}charite.de

ABSTRACT. Renal reabsorption of inorganic phosphate is mediated by the type IIa sodium phosphate cotransporter (NaPi-IIa) of the proximal tubule. Changes in renal phosphate handling are mainly attributable to altered NaPi-IIa brush border membrane (BBM) expression. Parathyroid hormone (PTH) induces inactivation of NaPi-IIa by endocytic membrane retrieval and degradation. The key elements triggering this process are not clear to date. Megalin serves as a receptor for the endocytosis of multiple ligands and is coexpressed with NaPi-IIa in the proximal tubule. Investigated was the role of megalin in the regulation of NaPi-IIa in steady state and during inactivation. Kidneys and tubular BBM fractions from mice with a renal-specific megalin gene defect and from controls were analyzed by light and electron microscopic histochemical techniques and Western blot test. Steady-state levels of NaPi-IIa in BBM were significantly enhanced, mRNA levels preserved, and phosphaturia reduced in the absence of megalin. Fluid-phase endocytosis was prevented and the apical endocytic apparatus markedly reduced. Systemic administration of PTH resulted in a defective retrieval and impaired degradation of NaPi-IIa. In vitro, the application of various stimuli of the PTH-induced signaling cascade had no effect either. Adequate steady-state expression of NaPi-IIa and the capacity of the proximal tubule cell to react on PTH-driven inactivation of NaPi-IIa by endocytosis and intracellular translocation require the presence of megalin.

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