| Budget Amount *help |
¥2,410,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
We investigated two system L amino acid transporters, LAT2 and LAT3 in the glomerulus. LAT2 and its functional ligand, 4F2hc, was expressed not only in the proximal tubules but also in the podocytes, however, its localization was revealed in the podocyte cytoplasm, suggesting that LAT2 does not function as amino acid transporter in normal mature podocytes. However, interestingly, LAT2 was dearly expressed in the cellular crescent lesion of human IgA nephropathy and ANCA-related glomerulonephritis. We further studied the role of LAT2 in the process of crescent formation by using rat crescent glomerulonephritis model. Increased phosphorylation of S6 ribosomal protein and 4E-BP1, down stream of mTOR pathway, was clearly demonstrated, preceding increase of LAT2 and 4F2hc expression in cellular crescents. LAT2 cDNA-transfected cell line exhibited predominant phosphorylation of p70S6K and 4E-BP1, which was clearly abrogated in the presence of LAT functional inhibitor. Taken together, we conc
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luded that upregulation of LAT2 and 4F2hc could be involved in the crescent formation via the mechanism by which mTOR signaling activated by growth factors and cytokines accelerated LAT2 and 4F2hc expression in the plasma membrane of glomerular parietal cells that leads secondary induction of mTOR signaling through increase of intra cellular branched-chain amino acids. On the other hand, LAT3 was clearly expressed in apical membrane of podocyte foot processes in human and mouse kidney. Cultured mouse podocytes exhibited system L amino acid transport system. Mouse LAT3 protein and mRNA were upregulated by food starvation. The human fatal kidney revealed LAT3 commencing expressing in the S-shaped body glomeruli Finally, zebrafish morphant lacking lat3 revealed collapsed glomerulus with thickened glomerular basement membrane, despite well-preserved slit diaphragm. Dye-injection experiment indicated the disruption of ultrafiltration barrier in zebrafish lat3 morphant Our data suggest that LAT3 plays a crucial role in glomerular development via the mechanism by which LAT3 transports leucine from the Bowman's space to podocyte cytoplasm, leading to the regulation of the protein synthesis system through mammalian target of rapamycin-2 activation. Less
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