Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain

Jazmin Chiu-Ugalde , Franziska Theilig , Thomas Behrends , Julia Drebes , Carolin Sieland , Prema Subbarayal , Josef Köhrle , Annette Hammes , Lutz Schomburg , Ulrich Schweizer (1)

1 Institut fur Experimentelle Endokrinologie

Distribution of selenium (Se) within the mammalian body is mediated by selenoprotein P (SePP), a Se-rich glycoprotein secreted by hepatocytes. Genetic and biochemical evidence indicate that the endocytic receptors ApoER2 and megalin mediate tissue-specific SePP uptake. Megalin-mutant mice were fed diets containing adequate (0.15 ppm) or low (0.08 ppm) Se content and were analyzed for tissue and plasma Se levels, cellular glutathione peroxidase (GPx) activities, and protein expression patterns. Megalin-mutant mice display increased urinary Se loss, which correlates with SePP excretion in their urine. Accordingly, serum Se and SePP are significantly reduced in megalin-mutant mice reaching marginal levels on the low Se diet. Moreover, kidney Se content and expression of renal selenoproteins are accordingly reduced as is SePP internalization along the proximal tubule epithelium. While GPx4 expression is not altered in testis, Se and GPx activity in liver and brain were significantly reduced. When fed a low Se diet, megalin-mutant mice develop impaired movement coordination, but no astrogliosis. Our findings suggest that megalin prevents urinary SePP loss and participates in brain Se/SePP uptake.

Mots clés: Life Sciences

Jazmin Chiu-Ugalde, Franziska Theilig, Thomas Behrends, Julia Drebes, Carolin Sieland, et al.. Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain. Biochemical Journal, 2010, 431 (1), pp.103-111. ⟨10.1042/BJ20100779⟩. ⟨hal-00517254⟩