Using affinity chromatography and surface plasmon resonance analysis, we ha
ve identified cubilin, a 460-kDa receptor heavily expressed in kidney proxi
mal tubule epithelial cells, as an albumin binding protein. Dogs with a fun
ctional defect in cubilin excrete large amounts of albumin in combination w
ith 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 l
ow-molecular-weight renal albumin binding proteins are fragments of cubilin
. In addition, we find that mice lacking the endocytic receptor megalin sho
w 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 prote
ins. This process may prove important for understanding interstitial renal
inflammation and fibrosis caused by proximal tubule uptake of an increased
load of filtered albumin.