Cubilin is an albumin binding protein important for renal tubular albumin reabsorption
Henrik Birn, John C. Fyfe, Christian Jacobsen, Francoise Mounier, Pierre J. Verroust, Hans Ørskov, Thomas E. Willnow, Søren K. Moestrup, Erik I. Christensen
Henrik Birn, John C. Fyfe, Christian Jacobsen, Francoise Mounier, Pierre J. Verroust, Hans Ørskov, Thomas E. Willnow, Søren K. Moestrup, Erik I. Christensen
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Cubilin is an albumin binding protein important for renal tubular albumin reabsorption

Abstract

Using affinity chromatography and surface plasmon resonance analysis, we have identified cubilin, a 460-kDa receptor heavily expressed in kidney proximal tubule epithelial cells, as an albumin binding protein. Dogs with a functional defect in cubilin excrete large amounts of albumin in combination with virtually abolished proximal tubule reabsorption, showing the critical role for cubilin in the uptake of albumin by the proximal tubule. Also, by immunoblotting and immunocytochemistry we show that previously identified low–molecular-weight renal albumin binding proteins are fragments of cubilin. In addition, we find that mice lacking the endocytic receptor megalin show altered urinary excretion, and reduced tubular reabsorption, of albumin. Because cubilin has been shown to colocalize and interact with megalin, we propose a mechanism of albumin reabsorption mediated by both of these proteins. This process may prove important for understanding interstitial renal inflammation and fibrosis caused by proximal tubule uptake of an increased load of filtered albumin.

Authors

Henrik Birn, John C. Fyfe, Christian Jacobsen, Francoise Mounier, Pierre J. Verroust, Hans Ørskov, Thomas E. Willnow, Søren K. Moestrup, Erik I. Christensen

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Colocalization of endogenous albumin, cubilin, and megalin in endocytic ...
Colocalization of endogenous albumin, cubilin, and megalin in endocytic compartments of normal rat proximal tubules. Section of rat kidney proximal tubule incubated with rabbit anti-rat albumin (1:10,000), sheep anti-rat megalin (1:50,000), and monoclonal mouse anti-rat cubilin (1:2,500) followed by incubation with gold conjugated goat anti-rabbit immunoglobulins (10 nm), donkey anti-sheep immunoglobulins (15 nm), and goat anti-mouse immunoglobulins (5 nm). Megalin (15-nm gold particles; arrows) and cubilin (5-nm gold particles; large arrowheads) colocalize (a) at the brush border (BB) and in endocytic vesicles (E) as well as in the recycling compartment dense apical tubules (D). Albumin (10-nm gold particles; small arrowheads) colocalize with the receptors in endocytic invaginations (I) and vesicles (E) and is concentrated in later endocytic compartments and lysosomes containing only little labeling for the receptors (b). Notice that most tubular structures (D) contain only labeling for the receptors supporting efficient recycling of these in contrast to albumin, which is degraded (b). ×58,000.