Kidney-specific inactivation of the megalin gene impairs trafficking of renal inorganic sodium phosphate cotransporter (NaPi-IIa).
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.
Bachmann
Sebastian
S
Department of Anatomy, Charité, University Medical School of Berlin, Campus Mitte, Philippstrasse 12, D-10098 Berlin, Germany. sbachm@charite.de
Schlichting
Uwe
U
Geist
Beate
B
Mutig
Kerim
K
Petsch
Thomas
T
Bacic
Desa
D
Wagner
Carsten A
CA
Kaissling
Brigitte
B
Biber
Jürg
J
Murer
Heini
H
Willnow
Thomas E
TE
D000818:Animals; D007668:Kidney / Q000378:metabolism* / Q000648:ultrastructure; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000494:pharmacology; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters / Q000187:drug effects / Q000378:metabolism*
D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010281:Parathyroid Hormone; C493555:Slc34a1 protein, mouse; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters