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

Abstract

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 β2-microglobulin (β2-m). Despite the use of high-flux membrane hemodialysis devices and direct absorbent columns, the removal of β2-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 β2-m. This study tested the feasibility of an intracorporeal therapeutic model of continuous β2-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 β2-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 with125I-β2-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