title: Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain.
abstract: Distribution of selenium (Se) within the mammalian body is mediated by SePP (selenoprotein P), an Se-rich glycoprotein secreted by hepatocytes. Genetic and biochemical evidence indicate that the endocytic receptors ApoER2 (apolipoprotein E receptor 2) and megalin mediate tissue-specific SePP uptake. In the present study megalin-mutant mice were fed on diets containing adequate (0.15 p.p.m.) or low (0.08 p.p.m.) Se content and were analysed for tissue and plasma Se levels, cellular GPx (glutathione peroxidase) activities and protein expression patterns. Megalin-mutant mice displayed increased urinary Se loss, which correlated with SePP excretion in their urine. Accordingly, serum Se and SePP levels were significantly reduced in megalin-mutant mice, reaching marginal levels on the low-Se diet. Moreover, kidney Se content and expression of renal selenoproteins were accordingly reduced, as was SePP internalization along the proximal tubule epithelium. Although GPx4 expression was not altered in testis, Se and GPx activity in liver and brain were significantly reduced. When fed on a low-Se diet, megalin-mutant mice developed impaired movement co-ordination, but no astrogliosis. These findings suggest that megalin prevents urinary SePP loss and participates in brain Se/SePP uptake.
authors.affiliation: Institut für Experimentelle Endokrinologie und EnForCé, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Jazmin
authors.initials: J
authors.lastname: Chiu-Ugalde
authors.forename: Franziska
authors.initials: F
authors.lastname: Theilig
authors.forename: Thomas
authors.initials: T
authors.lastname: Behrends
authors.forename: Julia
authors.initials: J
authors.lastname: Drebes
authors.forename: Carolin
authors.initials: C
authors.lastname: Sieland
authors.forename: Prema
authors.initials: P
authors.lastname: Subbarayal
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Annette
authors.initials: A
authors.lastname: Hammes
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D051381:Rats; D012643:Selenium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051149:Selenoprotein P / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D051149:Selenoprotein P; D005979:Glutathione Peroxidase; D012643:Selenium