title: Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease.
abstract: Injury to the glomerular podocyte is a key mechanism in human glomerular disease and podocyte repair is an important therapeutic target. In Fabry disease, podocyte injury is caused by the intracellular accumulation of globotriaosylceramide. This study identifies in the human podocyte three endocytic receptors, mannose 6-phosphate/insulin-like growth II receptor, megalin, and sortilin and demonstrates their drug delivery capabilities for enzyme replacement therapy. Sortilin, a novel α-galactosidase A binding protein, reveals a predominant intracellular expression but also surface expression in the podocyte. The present study provides the rationale for the renal effect of treatment with α-galactosidase A and identifies potential pathways for future non-carbohydrate based drug delivery to the kidney podocyte and other potential affected organs.
authors.affiliation: Section of Cell Biology, Department of Anatomy, Aarhus University, Aarhus, Denmark.
authors.forename: Thaneas
authors.initials: T
authors.lastname: Prabakaran
authors.forename: Rikke
authors.initials: R
authors.lastname: Nielsen
authors.forename: Jakob V
authors.initials: JV
authors.lastname: Larsen
authors.forename: Søren S
authors.initials: SS
authors.lastname: Sørensen
authors.forename: Ulla
authors.initials: U
authors.lastname: Feldt-Rasmussen
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Claus M
authors.initials: CM
authors.lastname: Petersen
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Verroust
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D015153:Blotting, Western; D002462:Cell Membrane; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D007457:Iodine Radioisotopes; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism*; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D007335:Insulin-Like Growth Factor II; D007457:Iodine Radioisotopes; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D014281:Trihexosylceramides; D000519:alpha-Galactosidase; D000099183:Sortilin; C018549:globotriaosylceramide