Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease

PLoS One. 2011;6(9):e25065. doi: 10.1371/journal.pone.0025065. Epub 2011 Sep 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Adult
  • Blotting, Western
  • Cell Membrane
  • Cells, Cultured
  • Endocytosis / physiology*
  • Fabry Disease / genetics
  • Fabry Disease / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Iodine Radioisotopes
  • Kidney / cytology
  • Kidney / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Male
  • Podocytes / cytology
  • Podocytes / metabolism*
  • RNA, Messenger / genetics
  • Receptor, IGF Type 2 / genetics
  • Receptor, IGF Type 2 / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Surface Plasmon Resonance
  • Trihexosylceramides / metabolism
  • alpha-Galactosidase / genetics
  • alpha-Galactosidase / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Iodine Radioisotopes
  • Low Density Lipoprotein Receptor-Related Protein-2
  • RNA, Messenger
  • Receptor, IGF Type 2
  • Recombinant Proteins
  • Trihexosylceramides
  • Insulin-Like Growth Factor II
  • globotriaosylceramide
  • alpha-Galactosidase
  • sortilin