Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain.
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.
Chiu-Ugalde
Jazmin
J
Institut für Experimentelle Endokrinologie und EnForCé, Charité-Universitätsmedizin, Berlin, Germany.
Theilig
Franziska
F
Behrends
Thomas
T
Drebes
Julia
J
Sieland
Carolin
C
Subbarayal
Prema
P
Köhrle
Josef
J
Hammes
Annette
A
Schomburg
Lutz
L
Schweizer
Ulrich
U
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
D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D051149:Selenoprotein P; D005979:Glutathione Peroxidase; D012643:Selenium