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Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria.

Author	Yaeko Motoyoshi, Taiji Matsusaka, Akihiko Saito, Ira Pastan, Thomas E Willnow, Shuki Mizutani, Iekuni Ichikawa
Citation Information	Kidney international, 74:1262-9 (2008)
Keywords	Absorption, Albumins, Animals, Female, Humans, Immunoglobulin A, Immunoglobulin G, Interleukin-2 Receptor alpha Subunit, Kidney Tubules, Proximal, LDL-Receptor Related Protein 2, Male, Mice, Mice, Knockout, Mice, Transgenic, Proteins, Proteinuria
Related Products	S7100
Pub Med ID	18769366

Megalin, a member of the LDL receptor family, is expressed on the apical membrane of proximal tubules and serves as an endocytic scavenger of filtered proteins and hence might contribute to the tubule injury as a consequence of glomerular disease. To study its role, we crossed megalin knockout mosaic mice (lacking megalin expression in 60% of proximal tubule cells) with NEP25 mice (a transgenic line expressing human CD25 in the podocyte). Treatment of this transgenic mouse with the immunotoxin causes nephrotic syndrome, focal segmental glomerulosclerosis and tubule-interstitial injury. Following this treatment, the double transgenic mice had massive non-selective proteinuria and mild glomerular and tubular injury. Comparison of megalin-containing to megalin-deficient proximal tubule cells within each kidney showed that albumin, immunoglobulin light chain, IgA and IgG were preferentially accumulated in proximal tubule cells expressing megalin. Tubule injury markers such as heme-oxygenase-1, monocyte chemoattractant protein-1 and cellular apoptosis were also preferentially found in these megalin-expressing cells. These results show that megalin plays a pivotal role in the reabsorption of small to large molecular size proteins and provides direct in vivo evidence that reabsorption of filtered proteins triggers events leading to tubule injury.