Evidence for the role of megalin in renal uptake of transthyretin
| Autor: | Pierre J. Verroust, Anthony G.W. Norden, Erik Ilsø Christensen, R. V. Thakker, Maria João Saraiva, Christian Jacobsen, Søren K. Moestrup, Mónica Mendes Sousa, Thomas E. Willnow |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
medicine.medical_specialty
endocrine system Heymann Nephritis Antigenic Complex Biology Kidney urologic and male genital diseases Biochemistry Kidney Tubules Proximal Mice Renal tubular dysfunction Internal medicine medicine Animals Humans Prealbumin Renal Insufficiency Receptor Molecular Biology Cells Cultured Yolk Sac Mice Knockout Membrane Glycoproteins Triiodothyronine Reabsorption nutritional and metabolic diseases Biological Transport Cell Biology LRP2 Recombinant Proteins Rats Retinol-Binding Proteins Thyroxine Transthyretin Kidney Tubules Endocrinology medicine.anatomical_structure Renal physiology biology.protein Retinol-Binding Proteins Plasma |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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