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Amino Acid Transporter LAT3 Is Required for Podocyte Development and Function

Yuji Sekine^*, Yukino Nishibori^*, Yoshihiro Akimoto, Akihiko Kudo, Noriko Ito^*, Daisuke Fukuhara^*, Ryota Kurayama^*, Eiji Higashihara, Ellappan Babu, Yoshikatsu Kanai, Katsuhiko Asanuma^||, Michio Nagata^¶, Årindam Majumdar^**, Karl Tryggvason^** and Kunimasa Yan^*

Departments of ^* Pediatrics, Anatomy, Urology, and Toxicology and Pharmacology, Kyorin University School of Medicine, Tokyo, Japan; ^|| Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan; ^¶ Department of Molecular Pathology, Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; and ^** Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institute, Stockholm, Sweden

Correspondence: Dr. Kunimasa Yan, Kyorin University School of Medicine, Department of Pediatrics, Mitaka, Tokyo 181-8611, Japan. Phone: +81-422-47-551; Fax: +81-422-47-8184; E-mail:kuniyanm{at}ks.kyorin-u.ac.jp

Received for publication July 31, 2008. Accepted for publication March 9, 2009.

LAT3 is a Na+-independent neutral L-amino acid transporter recently isolated from a human hepatocellular carcinoma cell line. Although liver, skeletal muscle, and pancreas are known to express LAT3, the tissue distribution and physiologic function of this transporter are not completely understood. Here, we observed that glomeruli express LAT3. Immunofluorescence, confocal microscopy, and immunoelectron microscopy revealed that LAT3 localizes to the apical plasma membrane of podocyte foot processes. In mice, starvation upregulated glomerular LAT3, phosphorylated AKT1, reconstituted the actin network, and elongated foot processes. In the fetal kidney, we observed intense LAT3 expression at the capillary loops stage of renal development. Finally, zebrafish morphants lacking lat3 function showed collapsed glomeruli with thickened glomerular basement membranes. Permeability studies of the glomerular filtration barrier in these zebrafish morphants demonstrated a disruption of selective glomerular permeability. Our data suggest that LAT3 may play a crucial role in the development and maintenance of podocyte structure and function by regulating protein synthesis and the actin cytoskeleton.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673