Distribution of α-Galactosidase A in Normal Human Kidney and Renal Accumulation and Distribution of Recombinant α-Galactosidase A in Fabry Mice

[摘要] Deficiency of lysosomal α-galactosidase A (α-Gal A) in Fabry disease results in cellular accumulation of globotriaosylceramide (Gl3), often leading to end-stage renal failure. Gl3 accumulates in endothelial, glomerular, and tubular cells. Replacement therapy with recombinant α-Gal A to some extent reduces cellular accumulation of Gl3 in the kidney. This study shows high lysosomal expression of α-Gal A in all tubular segments and interstitial cells of normal human kidney. However, glomeruli and endothelial cells did not express the enzyme to any significant extent. Recombinant enzyme was taken up by rat yolk sac cells in a receptor-associated protein–inhibitive manner, and surface plasmon resonance experiments revealed binding to megalin, indicating a possible mechanism for uptake of α-Gal A in the tubular cells. After infusion into experimental animals or patients, α-Gal A was recovered in the urine, indicating glomerular filtration. Recombinant α-Gal A was also found in kidneys of normal and α-Gal A knockout mice by Western blotting and localized to endosomes and lysosomes in proximal tubules, interstitial cells, and glomerular podocytes by immunocytochemistry and autoradiography but not in vascular endothelial cells. In conclusion, intravenously administered enzyme is taken up by interstitial cells, is to some extent filtered in glomeruli, and is taken up by podocytes and reabsorbed by receptor-mediated endocytosis in proximal tubule cells, directly indicating a potential beneficial effect of enzyme replacement therapy for these cells.

[学科分类] 泌尿医学

[关键词] Bone marrow necrosis;Sickle cell disease;Hyperhemolysis syndrome