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

Détails

ID Serval
serval:BIB_26654
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Impaired PTH-induced endocytotic down-regulation of the renal type IIa Na+/Pi-cotransporter in RAP-deficient mice with reduced megalin expression.
Périodique
Pflügers Archiv
Auteur(s)
Bacic D., Capuano P., Gisler S.M., Pribanic S., Christensen E.I., Biber J., Loffing J., Kaissling B., Wagner C.A., Murer H.
ISSN
0031-6768
Statut éditorial
Publié
Date de publication
2003
Volume
446
Numéro
4
Pages
475-484
Langue
anglais
Résumé
Inorganic phosphate (P(i)) reabsorption in the renal proximal tubule occurs mostly via the Na(+)/P(i) cotransporter type IIa (NaP(i)-IIa) located in the brush-border membrane (BBM) and is regulated, among other factors, by dietary P(i) intake and parathyroid hormone (PTH). The PTH-induced inhibition of P(i) reabsorption is mediated by endocytosis of Na/P(i)-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 NaP(i)-IIa and/or its regulation by dietary P(i) 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. NaP(i)-IIa protein distribution and abundance in the kidney was not altered. The localization and abundance of the NaP(i)-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 NaP(i)-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-P(i) diets appropriately as indicated by urinary P(i) excretion and NaP(i)-IIa protein abundance.
Mots-clé
Animals, Down-Regulation, Endocytosis, Kidney Tubules, Proximal, LDL-Receptor Related Protein 2, LDL-Receptor Related Protein-Associated Protein, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microvilli, Parathyroid Hormone, Phosphorus, Dietary, Sodium-Phosphate Cotransporter Proteins, Sodium-Phosphate Cotransporter Proteins, Type IIa, Symporters
Pubmed
Web of science
Création de la notice
19/11/2007 13:23
Dernière modification de la notice
20/08/2019 14:05
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