Mannose 6-phosphate receptor and sortilin mediated endocytosis of alpha-galactosidase A in kidney endothelial cells.
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Prabakaran T, Nielsen R, Satchell SC, Mathieson PW, Feldt-Rasmussen U, Sorensen SS, Christensen EI
Mannose 6-phosphate receptor and sortilin mediated endocytosis of alpha-galactosidase A in kidney endothelial cells.
PLoS One. 2012;7(6):e39975. doi: 10.1371/journal.pone.0039975. Epub 2012 Jun 29.
- PubMed ID
- 22768187 [ View in PubMed]
- Abstract
Prominent vasculopathy in Fabry disease patients is caused by excessive intracellular accumulation of globotriaosylceramide (GL-3) throughout the vascular endothelial cells causing progressive cerebrovascular, cardiac and renal impairments. The vascular lesions lead to myocardial ischemia, atherogenesis, stroke, aneurysm, thrombosis, and nephropathy. Hence, injury to the endothelial cells in the kidney is a key mechanism in human glomerular disease and endothelial cell repair is an important therapeutic target. We investigated the mechanism of uptake of alpha-galactosidase A (alpha-Gal A) in renal endothelial cells, in order to clarify if the recombinant enzyme is targeted to the lysosomes via the universal mannose 6-phosphate receptor (M6PR) and possibly other receptors. Immunohistochemical localization of infused recombinant alpha-Gal A in a renal biopsy from a classic Fabry disease patient showed that recombinant protein localize in the endothelial cells of the kidney. Affinity purification studies using alpha-Gal A resins identified M6PR and sortilin as alpha-Gal A receptors in cultured glomerular endothelial cells. Immunohistochemical analyses of normal human kidney with anti-sortilin and anti-M6PR showed that sortilin and M6PR were expressed in the endothelium of smaller and larger vessels. Uptake studies in cultured glomerular endothelial cells of alpha-Gal A labeled with fluorescence and (125)I showed by inhibition with RAP and M6P that sortilin and M6PR mediated uptake of alpha-Gal A. Biacore studies revealed that alpha-Gal A binds to human M6PR with very high affinity, but M6PR also binds to sortilin in a way that prevents alpha-Gal A binding to sortilin. Taken together, our data provide evidence that sortilin is a new alpha-Gal A receptor expressed in renal endothelial cells and that this receptor together with the M6PR is able to internalize circulating alpha-Gal A during enzyme replacement therapy in patients with Fabry disease.
DrugBank Data that Cites this Article
- Drugs
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Agalsidase beta Cation-dependent mannose-6-phosphate receptor Protein Humans UnknownSubstrateDetails