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Kidney-specific inactivation of the megalin gene impairs trafficking of renal inorganic sodium phosphate cotransporter (NaPi-IIa)

Item Type:Article
Title:Kidney-specific inactivation of the megalin gene impairs trafficking of renal inorganic sodium phosphate cotransporter (NaPi-IIa)
Creators Name:Bachmann, S. and Schlichting, U. and Geist, B. and Mutig, K. and Petsch, T. and Bacic, D. and Wagner, C.A. and Kaissling, B. and Biber, J. and Murer, H. and Willnow, T.E.
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.
Keywords:Kidney, LDL-Receptor Related Protein 2, Parathyroid Hormone, Sodium-Phosphate Cotransporter Proteins, Symporters, Type IIa Sodium-Phosphate Cotransporter Proteins, Animals, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology (U.S.A.)
Page Range:892-900
Date:1 April 2004
Official Publication:https://doi.org/10.1097/01.ASN.0000120389.09938.21
PubMed:View item in PubMed

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