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Cubilin is essential for albumin reabsorption in the renal proximal tubule

Item Type:Article
Title:Cubilin is essential for albumin reabsorption in the renal proximal tubule
Creators Name:Amsellem, S. and Gburek, J. and Hamard, G. and Nielsen, R. and Willnow, T.E. and Devuyst, O. and Nexo, E. and Verroust, P.J. and Christensen, E.I. and Kozyraki, R.
Abstract:Receptor-mediated endocytosis is responsible for protein reabsorption in the proximal tubule. This process involves two interacting receptors, megalin and cubilin, which form a complex with amnionless. Whether these proteins function in parallel or as part of an integrated system is not well understood. Here, we report the renal effects of genetic ablation of cubilin, with or without concomitant ablation of megalin, using a conditional Cre-loxP system. We observed that proximal tubule cells did not localize amnionless to the plasma membrane in the absence of cubilin, indicating a mutual dependency of cubilin and amnionless to form a functional membrane receptor complex. The cubilin-amnionless complex mediated internalization of intrinsic factor-vitamin B12 complexes, but megalin considerably increased the uptake. Furthermore, cubilin-deficient mice exhibited markedly decreased uptake of albumin by proximal tubule cells and resultant albuminuria. Inactivation of both megalin and cubilin did not increase albuminuria, indicating that the main role of megalin in albumin reabsorption is to drive the internalization of cubilin-albumin complexes. In contrast, cubulin deficiency did not affect urinary tubular uptake or excretion of vitamin D-binding protein (DBP), which binds cubilin and megalin. In addition, we observed cubilin-independent reabsorption of the "specific" cubilin ligands transferrin, CC16, and apoA-I, suggesting a role for megalin and perhaps other receptors in their reabsorption. In summary, with regard to albumin, cubilin is essential for its reabsorption by proximal tubule cells, and megalin drives internalization of cubilin-albumin complexes. These genetic models will allow further analysis of protein trafficking in the progression of proteinuric renal diseases.
Keywords:Absorption, Albumins, DNA-Binding Proteins, Integrases, Proximal Kidney Tubules, LDL-Receptor Related Protein 2, Proteinuria, Cell Surface Receptors, Transcription Factors, Vitamin B 12, Animals, Mice
Source:Journal of the American Society of Nephrology
ISSN:1046-6673
Publisher:American Society of Nephrology (U.S.A.)
Volume:21
Number:11
Page Range:1859-1867
Date:November 2010
Official Publication:https://doi.org/10.1681/ASN.2010050492
PubMed:View item in PubMed

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