1. ¹Department of Bioethics, Tokai University School of Medicine, Isehara City, Kanagawa, Japan
2. ²Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
3. ³Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
4. ⁴Department of Internal Medicine, Tokai University School of Medicine, Isehara City, Kanagawa, Japan
5. ⁵Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Niigata, Japan
6. ⁶Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
7. ⁷Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

Correspondence: Iekuni Ichikawa, Iekuni Ichikawa, Department of Bioethics, Tokai University School of Medicine, 143 Shimo-kasuya, Isehara City, Kanagawa 259-1193, Japan; Iekuni Ichikawa, Department of Pediatrics, Vanderbilt University Medical Center, 1161 21st Avenue, Nashville, Tennessee 37212, USA. E-mail: ichikawaMD@aol.com

Received 24 March 2008; Revised 26 May 2008; Accepted 10 June 2008; Published online 3 September 2008.

Abstract

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.