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, Erik I. Christensen

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2458-2467
Number of pages10
JournalNephrology Dialysis Transplantation
Volume25
Issue number8
DOIs
StatePublished - Aug 2010

Bibliographical note

Funding Information:
Acknowledgements. The authors thank Hanne Sidelmann, Pia Kamuk Nielsen, Anne Merete Hass, Inger Blenker Kristoffersen and Mary Sanders for excellent technical assistance. The study was presented in part at the ASN Annual meeting 2005, Philadelphia, PA, USA, November 2005 and published in part as abstract. The work was supported in part by the Danish Medical Research Council, the University of Aarhus, the NOVO-Nordisk Foundation, the Mogens S. Mogensens Foundation, the Biomem-brane Research Center, the European Commission (EU FP6, EuReGene, GA#5085, and FP7, EUNEFRON, GA#201590) and the National Institutes of Health (DK 57676 and DK 64273).

Keywords

  • alport syndrome
  • cubilin
  • glomerular disease
  • megalin
  • proteinuria

Fingerprint

Dive into the research topics of 'The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney'. Together they form a unique fingerprint.

Cite this