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Role of Megalin in Endocytosis of Advanced Glycation End Products: Implications for a Novel Protein Binding to Both Megalin and Advanced Glycation End Products

Akihiko Saito^*, Ryoji Nagai, Atsuhito Tanuma^*, Hitomi Hama^*, Kenji Cho^*, Tetsuro Takeda^*, Yutaka Yoshida, Tosifusa Toda, Fujio Shimizu^¶, Seikoh Horiuchi and Fumitake Gejyo^*

*Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Biochemistry, Kumamoto University School of Medicine, Kumamoto, Japan; Department of Renal Pathology, Institute of Nephrology, Faculty of Medicine, Niigata University, Niigata, Japan; Department of Gene Regulation and Protein Function, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan; and ^¶Department of Cell Biology, Institute of Nephrology, Faculty of Medicine, Niigata University, Niigata, Japan.

Correspondence to Dr. Akihiko Saito, Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan. Phone: 81-25-227-2200; Fax: 81-25-227-0775;

ABSTRACT. Advanced glycation end products (AGE) are filtered by glomeruli and reabsorbed and metabolized by proximal tubule cells (PTC). In renal failure, decreased renal AGE metabolism likely accounts for the accumulation in serum that is related to uremic complications. In diabetes, AGE generation is increased, and the handling mechanisms in PTC are likely associated with the pathogenesis of tubulointerstitial injury. It is therefore important to clarify the mechanisms of the AGE metabolism to develop a strategy for removing AGE in uremia and to elucidate the pathogenesis of diabetic nephropathy. To this end, this study focused on the molecular analysis of megalin, a multi-ligand endocytic receptor, in PTC. AGE uptake analysis was performed using the rat yolk sac-derived L2 cell line system established for the analysis of megalin’s endocytic functions. The cells mediated specific internalization and degradation of AGE, which were significantly blocked by anti-megalin IgG, indicating that megalin is involved in the cellular processes. However, cell surface AGE-binding assays and ligand blot analysis revealed no evidence that megalin is a direct AGE receptor. Affinity chromatography and ligand blot analysis originally revealed that 200-kD and 400-kD proteins in the cells bind to AGE and the 200-kD protein to megalin in a Ca²⁺-dependent manner. The binding of megalin with the 200-kD protein was suppressed by receptor-associated protein (RAP), a ligand for megalin. In conclusion, megalin functions for endocytosis of AGE via an indirect mechanism. L2 cells express novel AGE-binding proteins, one of which may interact with megalin. E-mail: akisaito@med.niigata-u.ac.jp

This article has been cited by other articles:

				J. M. Bohlender, S. Franke, G. Stein, and G. Wolf Advanced glycation end products and the kidney Am J Physiol Renal Physiol, October 1, 2005; 289(4): F645 - F659. [Abstract] [Full Text] [PDF]

				H. Hama, A. Saito, T. Takeda, A. Tanuma, Y. Xie, K. Sato, J. J. Kazama, and F. Gejyo Evidence Indicating that Renal Tubular Metabolism of Leptin Is Mediated by Megalin But Not by the Leptin Receptors Endocrinology, August 1, 2004; 145(8): 3935 - 3940. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673