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J Am Soc Nephrol 14:2025-2032, 2003
© 2003 American Society of Nephrology

Bioengineered Implantation of Megalin-Expressing Cells: A Potential Intracorporeal Therapeutic Model for Uremic Toxin Protein Clearance in Renal Failure

Akihiko Saito*,{dagger}, Junichiro J. Kazama{dagger}, Noriaki Iino{dagger}, Kenji Cho{dagger}, Nobuo Sato{dagger}, Hajime Yamazaki{dagger}, Yuko Oyama{dagger}, Tetsuro Takeda*,{dagger}, Robert A. Orlando§, Fujio Shimizu{ddagger}, Yasuhiko Tabata|| and Fumitake Gejyo{dagger}

*Department of Applied Molecular Medicine, {dagger}Division of Clinical Nephrology and Rheumatology, and {ddagger}Division of Cell Biology, Department of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; §Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico, Albuquerque, New Mexico; and ||Department of Biomaterials, Institute of Frontier Medical Sciences, Kyoto University, Kyoto, Japan.

Correspondence to Akihiko Saito, Department of Applied Molecular Medicine, 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. Patients who have renal failure and are on dialysis therapy experience serious complications caused by low-molecular-weight uremic toxin proteins normally filtered by glomeruli and metabolized by proximal tubule cells (PTC). Dialysis-related amyloidosis is one such complication induced by systemic deposition of amyloid proteins derived from 12-kD {beta}2-microglobulin ({beta}2-m). Despite the use of high-flux membrane hemodialysis devices and direct absorbent columns, the removal of {beta}2-m is suboptimal, because the effects are transient and insufficient. Megalin is expressed in the apical membranes of PTC and recognized as a multiligand endocytic receptor that binds numerous low-molecular-weight proteins, including {beta}2-m. This study tested the feasibility of an intracorporeal therapeutic model of continuous {beta}2-m removal using megalin-expressing cell implantation. By cell association and degradation assays, rat yolk sac-derived L2 cells were identified to internalize and degrade {beta}2-m via megalin. The cells were effectively implanted within the subcutaneous tissues of nude mice using a type I collagen scaffold and a method inducing local angiogenesis. After nephrectomy and intraperitoneal injection with 125I-{beta}2-m, it was found that the implanted cells took up the labeled ligand, efficiently removing it from the blood. Bioengineered implantation of megalin-expressing cells may represent a new supportive therapy for dialysis patients to compensate for the loss of renal protein metabolism and remove uremic toxin proteins. E-mail: akisaito@med.niigata-u.ac.jp




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