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.
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.
Authors: S K Moestrup; R Kozyraki; M Kristiansen; J H Kaysen; H H Rasmussen; D Brault; F Pontillon; F O Goda; E I Christensen; T G Hammond; P J Verroust Journal: J Biol Chem Date: 1998-02-27 Impact factor: 5.157
Authors: E I Christensen; S Nielsen; S K Moestrup; C Borre; A B Maunsbach; E de Heer; P Ronco; T G Hammond; P Verroust Journal: Eur J Cell Biol Date: 1995-04 Impact factor: 4.492
Authors: Jennifer R Charlton; Weizhen Tan; Ghaleb Daouk; Lisa Teot; Seymour Rosen; Kevin M Bennett; Aleksandra Cwiek; Sejin Nam; Francesco Emma; François Jouret; João Paulo Oliveira; Lisbeth Tranebjærg; Carina Frykholm; Shrikant Mane; Friedhelm Hildebrandt; Tarak Srivastava; Tina Storm; Erik Ilsø Christensen; Rikke Nielsen Journal: Am J Physiol Renal Physiol Date: 2020-10-26
Authors: Thaneas Prabakaran; Rikke Nielsen; Simon C Satchell; Peter W Mathieson; Ulla Feldt-Rasmussen; Søren S Sørensen; Erik I Christensen Journal: PLoS One Date: 2012-06-29 Impact factor: 3.240
Authors: Evgenia Dobrinskikh; Linda Lewis; R Brian Doctor; Kayo Okamura; Min Goo Lee; Christopher Altmann; Sarah Faubel; Jeffrey B Kopp; Judith Blaine Journal: Physiol Rep Date: 2015-09