The kidney is a major organ for uptake of the
thyroid hormone thyroxine (T(4)) and its conversion to the active form,
triiodothyronine. In the plasma, one of the T(4) carriers is
transthyretin (TTR). In the present study we observed that TTR, the transporter of both T(4) 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 T(4)-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.