The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney.
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.
Vinge
Lotte
L
Cell Biology, Department of Anatomy, Aarhus University, Aarhus, Denmark. lv@ana.au.dk
Lees
George E
GE
Nielsen
Rikke
R
Kashtan
Clifford E
CE
Bahr
Anne
A
Christensen
Erik I
EI
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D005919:Glomerular Filtration Rate / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008247:Lysosomes / Q000473:pathology; D008297:Male; D009394:Nephritis, Hereditary / Q000378:metabolism* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism
D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor