title: Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12).
abstract: Megalin has previously been shown to bind and mediate endocytosis of transcobalamin (TC)-B(12). However, the physiological significance of this has not been established, and other TC-B(12) 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 B(12) and for renal accumulation of this highly conserved vitamin. Megalin-deficient mice excrete increased amounts of TC and B(12) in the urine, revealing a defective renal tubular uptake of TC-B(12). The urinary B(12) excretion is increased approximately 4-fold, resulting in an approximately 28-fold higher renal B(12) clearance. This is associated with an approximately 4-fold decrease in B(12) content in megalin-deficient kidney cortex. Thus megalin is important to prevent urinary loss of vitamin B(12). In addition, light- and electron-microscopic immunocytochemistry demonstrate lysosomal accumulation of B(12) in rat and mouse proximal tubules. In rats this accumulation is correlated with vitamin intake. Thus renal lysosomal B(12) accumulation is dependent on vitamin status, indicating a possible reserve function of this organelle in the rat kidney.
authors.affiliation: Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus C, Germany. hb@ana.au.dk
authors.forename: Henrik
authors.initials: H
authors.lastname: Birn
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Rikke
authors.initials: R
authors.lastname: Nielsen
authors.forename: Anthony G W
authors.initials: AG
authors.lastname: Norden
authors.forename: Christian
authors.initials: C
authors.lastname: Bönsch
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
authors.forename: Ebba
authors.initials: E
authors.lastname: Nexø
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001692:Biological Transport / Q000502:physiology; D003404:Creatinine / Q000032:analysis / Q000378:metabolism; D004032:Diet; D004705:Endocytosis / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D014155:Transcobalamins / Q000032:analysis / Q000378:metabolism*; D014508:Urea / Q000032:analysis / Q000378:metabolism; D014805:Vitamin B 12 / Q000032:analysis / Q000276:immunology / Q000493:pharmacokinetics*
chemical_list: D000911:Antibodies, Monoclonal; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D014155:Transcobalamins; D014508:Urea; D003404:Creatinine; D014805:Vitamin B 12