title: Bioengineered implantation of megalin-expressing cells: a potential intracorporeal therapeutic model for uremic toxin protein clearance in renal failure.
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 (125)I-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.
authors.affiliation: Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. akisaito@med.niigata-u.ac.jp
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
authors.forename: Junichiro J
authors.initials: JJ
authors.lastname: Kazama
authors.forename: Noriaki
authors.initials: N
authors.lastname: Iino
authors.forename: Kenji
authors.initials: K
authors.lastname: Cho
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sato
authors.forename: Hajime
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oyama
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Takeda
authors.forename: Robert A
authors.initials: RA
authors.lastname: Orlando
authors.forename: Fujio
authors.initials: F
authors.lastname: Shimizu
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
mesh_terms: D000818:Animals; D001698:Biomedical Engineering / Q000379:methods*; D024042:Collagen Type I / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004705:Endocytosis; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D007687:Kidney Tubules, Proximal; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000473:pathology*; D013997:Time Factors; D014118:Toxins, Biological / Q000378:metabolism*; D014511:Uremia / Q000378:metabolism; D015017:Yolk Sac / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D008024:Ligands; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011994:Recombinant Proteins; D014118:Toxins, Biological; D001613:beta 2-Microglobulin