Cubilin is essential for albumin reabsorption in the renal proximal tubule.
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.
Amsellem
Sabine
S
INSERM UMR S968, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
Gburek
Jakub
J
Hamard
Ghislaine
G
Nielsen
Rikke
R
Willnow
Thomas E
TE
Devuyst
Olivier
O
Nexo
Ebba
E
Verroust
Pierre J
PJ
Christensen
Erik I
EI
Kozyraki
Renata
R
D000042:Absorption; D000418:Albumins / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D019426:Integrases / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011507:Proteinuria / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism
D000418:Albumins; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C029486:intrinsic factor-cobalamin receptor; C045073:Cre recombinase; D019426:Integrases; D014805:Vitamin B 12
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