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This Article Full Text Full Text (PDF) All Versions of this Article: 285/3/F451    most recent 00062.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Gburek, J. Articles by Christensen, E. I. Search for Related Content PubMed PubMed Citation Articles by Gburek, J. Articles by Christensen, E. I.

Renal uptake of myoglobin is mediated by the endocytic receptors megalin and cubilin

Departments of ¹Cell Biology and ⁴Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark; ²Department of Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, 50139 Wroclaw, Poland; ³Institut Nationale de la Santé et de la Recherche Medicalé Unité 538, Centre Hospitalier Universitaire, St. Antoine, 75012 Paris, France; and ⁵Max Delbrueck Center for Molecular Medicine, D-13125 Berlin, Germany

Submitted 14 February 2003 ; accepted in final form 16 April 2003

Nephrotoxicity of myoglobin is well recognized as playing a part in the development of acute renal failure in settings of myoglobinuria. However, the molecular mechanism of myoglobin uptake in renal proximal tubules has not been clarified. Here, we report that the endocytic receptors megalin and cubilin are involved in renal reabsorption of myoglobin. Both receptors were captured from solubilized renal brush-border membranes by affinity chromatography using myoglobin-Sepharose. Myoglobin bound to purified megalin and cubilin with K_d values of 2.0 and 3 µM, respectively, as evaluated by surface plasmon resonance analysis. Apomyoglobin bound to megalin with the same affinity, and the affinity of apomyoglobin to cubilin was reduced (K_d = 5 µM). Radioiodinated myoglobin could be displaced by apomyoglobin in inhibition studies using isolated renal brush-border membranes (K_i 2 µM). Receptor-associated protein as well as antibodies directed against megalin and cubilin markedly inhibited the uptake of fluorescent-labeled myoglobin by cultured yolk sac BN-16 cells. The significance of megalin- and cubilin-mediated endocytosis for myoglobin uptake in vivo was demonstrated by use of kidney-specific megalin knockout mice. Injected myoglobin was extensively reabsorbed by megalin-expressing proximal tubular cells, whereas there was very little uptake in the megalin-deficient cells. In conclusion, this study establishes the molecular mechanism of myoglobin uptake in the renal proximal tubule involving the endocytic receptors megalin and cubilin. Identification of the receptors for tubular uptake of myoglobin may be essential for development of new therapeutic strategies for myoglobinuric acute renal failure.

endocytosis; acute renal failure

This article has been cited by other articles:

				J. Nagai, E. I. Christensen, S. M. Morris, T. E. Willnow, J. A. Cooper, and R. Nielsen Mutually dependent localization of megalin and Dab2 in the renal proximal tubule Am J Physiol Renal Physiol, September 1, 2005; 289(3): F569 - F576. [Abstract] [Full Text] [PDF]