Cubilin is essential for albumin reabsorption in the renal proximal tubule

INSERM UMR S968, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
Journal of the American Society of Nephrology (Impact Factor: 9.47). 11/2010; 21(11):1859-67. DOI: 10.1681/ASN.2010050492
Source: PubMed

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.

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Available from: Rikke Nielsen, Aug 26, 2015
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    • "Albumin is reabsorbed from the filtrate via a constitutive receptor mediated endocytic pathway . Cubilin binds albumin, with the associated transmembrane receptor megalin required for endocytosis of the albumin/cubilin complex (Amsellem et al., 2010). Following internalisation, degradation of the ligand is achieved by vesicular acidification via the chlorine channel 5 and the Na + H + exchanger 3 (Christensen et al., 2009). "
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    • "It is clear that albumin uptake in the proximal tubule cell is subject to regulation by a number of different pathways and it is likely that other molecular interactions may predominate to retain normal function when one of the components is eliminated. Cubilin is essential for albumin binding, however megalin drives internalisation of this complex (Amsellem et al., 2010). Therefore it is critical to understand how megalin itself interacts with and is regulated by other proteins. "
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