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1 Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C; 2 Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany; 3 Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2QR, United Kingdom; 4 Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C; and 5 Department of Clinical Biochemistry, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
Megalin has previously been shown to bind and mediate endocytosis of transcobalamin (TC)-B12. However, the physiological significance of this has not been established, and other TC-B12 binding proteins have been suggested to mediate renal uptake of this vitamin complex. The present study demonstrates by the use of megalin-deficient mice that megalin is, in fact, essential for the normal renal reabsorption of TC-vitamin B12 and for renal accumulation of this highly conserved vitamin. Megalin-deficient mice excrete increased amounts of TC and B12 in the urine, revealing a defective renal tubular uptake of TC-B12. The urinary B12 excretion is increased ~4-fold, resulting in an ~28-fold higher renal B12 clearance. This is associated with an ~4-fold decrease in B12 content in megalin-deficient kidney cortex. Thus megalin is important to prevent urinary loss of vitamin B12. In addition, light- and electron-microscopic immunocytochemistry demonstrate lysosomal accumulation of B12 in rat and mouse proximal tubules. In rats this accumulation is correlated with vitamin intake. Thus renal lysosomal B12 accumulation is dependent on vitamin status, indicating a possible reserve function of this organelle in the rat kidney.
kidney; receptor-mediated endocytosis; cobalamin; lysosomes; immunocytochemistry
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