Journal Article

The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney

Lotte Vinge, George E. Lees, Rikke Nielsen, Clifford E. Kashtan, Anne Bahr and Erik I. Christensen

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 25, issue 8, pages 2458-2467
Published in print August 2010 | ISSN: 0931-0509
Published online March 2010 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfq044
The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney

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Background. A well-characterized dog model of the X-linked collagen disease Alport syndrome (XLAS) was used to study the effect of progressive glomerular disease on megalin-mediated endocytosis. In XLAS, altered structure and function of the glomerular basement membrane induces a progressive proteinuric nephropathy.

Methods. The investigation was performed in male XLAS dogs and age-matched normal male littermates. The urine profile and megalin-mediated endocytosis in the proximal tubule of six healthy and six XLAS dogs were examined at 2, 4, 6, 8 and 10 months of age using SDS–PAGE, immunoblotting and immunohistochemistry.

Results. Gradually increasing urinary excretion of proteins over time and a reduced content of the same proteins in proximal tubule cells were found. Besides the glomerular component of the proteinuria, a significant tubular component was seen, which is due to a progressive change in the uptake of low-molecular-weight (LMW) ligands by megalin. Furthermore, the protein overload present in the lumen of the proximal tubule exceeds the reabsorption capacity of megalin and the co-receptor cubilin and results in a combined low- and high-molecular-weight (HMW) proteinuria. Also, a shift in the distribution of lysosomes was seen in the XLAS dogs suggesting changes in the lysosomal degradation pattern in response to the altered endocytosis.

Conclusions. The present study shows that the increased glomerular permeability and the subsequently altered megalin-mediated and megalin-dependent cubilin-mediated endocytosis lead to a partial LMW proteinuria and partial HMW proteinuria.

Keywords: alport syndrome; cubilin; glomerular disease; megalin; proteinuria

Journal Article.  6067 words.  Illustrated.

Subjects: Nephrology

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