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J. Biol. Chem., Vol. 283, Issue 11, 6854-6860, March 14, 2008

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Megalin Mediates Selenoprotein P Uptake by Kidney Proximal Tubule Epithelial Cells^*

Gary E. Olson¹, Virginia P. Winfrey, Kristina E. Hill, and Raymond F. Burk

From the Department of Cell and Developmental Biology and the Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Selenoprotein P (Sepp1) contains most of the selenium in blood plasma, and it is utilized by the kidney, brain, and testis as a selenium source for selenoprotein synthesis. We recently demonstrated that apolipoprotein E receptor-2 (ApoER2) is required for Sepp1 uptake by the testis and that deletion of ApoER2 reduces testis and brain, but not kidney, selenium levels. This study examined the kidney Sepp1 uptake pathway. Immunolocalization experiments demonstrated that Sepp1 passed into the glomerular filtrate and was specifically taken up by proximal tubule epithelial cells. Neither the C terminus selenocysteine-rich domain of Sepp1 nor ApoER2 was required for Sepp1 uptake by proximal tubules. Tissue ligand binding assays using cryosections of Sepp1^-/- kidneys revealed that the proximal tubule epithelium contained Sepp1-binding sites that were blocked by the receptor-associated protein, RAP, an inhibitor of lipoprotein receptor-ligand interactions. Ligand blotting assays of kidney membrane preparations fractionated by SDS-PAGE revealed that Sepp1 binds megalin, a lipoprotein receptor localized to the proximal tubule epithelium. Immunolocalization analyses confirmed the in vivo co-localization of Sepp1 and megalin in wild type kidneys and demonstrated the absence of proximal tubule Sepp1 uptake in megalin null mice. These results demonstrate that kidney selenium homeostasis is mediated by a megalin-dependent Sepp1 uptake pathway in the proximal tubule.

Received for publication, December 5, 2007 , and in revised form, January 3, 2008.

^* This work was supported by National Institutes of Health Grants HD044863 and ES02497. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Fax: 615-343-9484; E-mail: gary.olson{at}vanderbilt.edu.

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