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Megalin−/− mice excrete N‐terminal fragments of selenoprotein P (Sepp1) in urine
Author(s) -
Kurokawa Suguru,
McDonald W. Hayes,
Hill Kristina E.,
Burk Raymond F.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.100.2
Subject(s) - selenoprotein p , chemistry , selenocysteine , gpx3 , selenoprotein , selenium , medicine , endocytosis , kidney , endocrinology , receptor , microbiology and biotechnology , glutathione peroxidase , biochemistry , biology , glutathione , enzyme , cysteine , organic chemistry
Sepp1 transports selenium from the liver to other tissues via the plasma. Apolipoprotein E receptor‐2 facilitates Sepp1 uptake by brain and testis. Megalin, a related receptor located on the apical membrane of renal proximal convoluted tubule (PCT) cells, binds glomerular filtrate proteins for endocytosis. Sepp1, detected by an antibody (9S4) to its selenium‐poor N‐terminal domain, is endocytosed by PCT cells in a megalin‐dependent manner. Because of its large size, full‐length Sepp1 would not be expected to appear in the glomerular filtrate. Megalin −/− mice were studied to assess the nature of Sepp1 in their urine. They were injected with 75 SeO 3 2− . Urine was analyzed by SDS/PAGE autoradiography. Several 75 Se‐labeled bands appeared in the urine of megalin −/− mice but not megalin +/+ mice. One bound to an antibody to glutathione peroxidase‐3 (Gpx3). Several bound to 9S4 but one did not bind to either antibody. LC‐MS/MS identified one band as Gpx3 and all others as N‐terminal fragments of Sepp1, each containing only one selenocysteine. Also, knockout of megalin decreased kidney selenium and plasma Gpx activity. We postulate that the selenium‐rich C‐terminal domain of Sepp1 is removed in the body and the resulting N‐terminal fragments are filtered and taken up by PCT cells, supplying selenium for Gpx3 synthesis. Supported by NIH grant ES02497.