title: Megalin knockout mice as an animal model of low molecular weight proteinuria.
abstract: Megalin is an endocytic receptor expressed on the luminal surface of the renal proximal tubules. The receptor is believed to play an important role in the tubular uptake of macromolecules filtered through the glomerulus. To elucidate the role of megalin in vivo and to identify its endogenous ligands, we analyzed the proximal tubular function in mice genetically deficient for the receptor. We demonstrate that megalin-deficient mice exhibit a tubular resorption deficiency and excrete low molecular weight plasma proteins in the urine (low molecular weight proteinuria). Proteins excreted include small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, alpha(1)-microglobulin and odorant-binding protein. Megalin binds these proteins and mediates their cellular uptake. Urinary loss of carrier proteins in megalin-deficient mice results in concomitant loss of lipophilic vitamins bound to the carriers. Similar to megalin knockout mice, patients with low molecular weight proteinuria as in Fanconi syndrome are also shown to excrete vitamin/carrier complexes. Thus, these results identify a crucial role of the proximal tubule in retrieval of filtered vitamin/carrier complexes and the central role played by megalin in this process.
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors.forename: J R
authors.initials: JR
authors.lastname: Leheste
authors.forename: B
authors.initials: B
authors.lastname: Rolinski
authors.forename: H
authors.initials: H
authors.lastname: Vorum
authors.forename: J
authors.initials: J
authors.lastname: Hilpert
authors.forename: A
authors.initials: A
authors.lastname: Nykjaer
authors.forename: C
authors.initials: C
authors.lastname: Jacobsen
authors.forename: P
authors.initials: P
authors.lastname: Aucouturier
authors.forename: J O
authors.initials: JO
authors.lastname: Moskaug
authors.forename: A
authors.initials: A
authors.lastname: Otto
authors.forename: E I
authors.initials: EI
authors.lastname: Christensen
authors.forename: T E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D005198:Fanconi Syndrome / Q000235:genetics / Q000652:urine; D005260:Female; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D007678:Kidney Glomerulus / Q000276:immunology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008871:Microvilli / Q000648:ultrastructure; D008969:Molecular Sequence Data; D011485:Protein Binding; D011507:Proteinuria / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D017421:Sequence Analysis; D016482:Urinalysis; D014815:Vitamins / Q000652:urine
chemical_list: D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; D014815:Vitamins