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J. Biol. Chem., Vol. 275, Issue 49, 38176-38181, December 8, 2000
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From the a Amyloid Unit, Instituto de Biologia
Molecular e Celular and the b Instituto de Ciências
Biomédicas Abel Salazar, University of Porto, Porto 4150, Portugal, the d Department of Clinical Biochemistry,
Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, United
Kingdom, the Departments of e Medical Biochemistry and
g Cell Biology, University of Aarhus, 8000 Aarhus C,
Denmark, the f Max-Delbrueck Center for Molecular Medicine,
13125 Berlin, Germany, the h Molecular Endocrinology Group,
Nuffield Department of Medicine, University of Oxford,
Oxford OX3 9DU, United Kingdom, and the i INSERM, U489,
Hôpital Tenon, F-75020 Paris, France
The kidney is a major organ for
uptake of the thyroid hormone thyroxine (T4) and its
conversion to the active form, triiodothyronine. In the plasma,
one of the T4 carriers is transthyretin (TTR). In the
present study we observed that TTR, the transporter of both
T4 and retinol-binding protein, binds to megalin, the
multiligand receptor expressed on the luminal surface of various
epithelia including the renal proximal tubules. In the kidney, megalin
plays an important role in tubular uptake of macromolecules filtered through the glomerulus. To evaluate the importance of megalin for renal
uptake of TTR, we performed binding/uptake assays using immortalized
rat yolk sac cells with high expression levels of megalin. Radiolabeled
TTR, free as well as in complex with thyroxine or retinol-binding
protein, was rapidly taken up by the cells, and the uptake was strongly
inhibited by a polyclonal megalin antibody and by the
receptor-associated protein, a chaperone-like protein inhibiting ligand
binding to megalin. In cell culture, different TTR mutations presented
different levels of cell association and degradation, suggesting that
the structure of TTR is important for megalin recognition. Both the apo
form and the T4-bound form were taken up by the cells.
Analysis of urine from patients with Dent's disease, a renal tubular
disorder that alters receptor-mediated endocytic reabsorption of
proteins, identified TTR as an abundant excreted protein. Furthermore,
analysis of kidney sections of megalin-deficient mice revealed no
immunohistochemical TTR labeling in intracellular vesicles in the
proximal tubule cells when compared with wild type control littermates.
Taken together, the present data indicate that TTR represents a novel
megalin ligand of importance in the thyroid hormone homeostasis.
Evidence for the Role of Megalin in Renal Uptake of
Transthyretin*
*
This work was supported by grants from PRAXIS XXI
(2/2.1/BIA/459/94) from Portugal (to M. J. S.), the Novo Nordisk
Foundation, the Danish Biotechnology Program, and the University of
Aarhus (to S. K. M.), and the Sir Jules Thorn Charitable Fund
(to A. G. W. N.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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