| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
TGF-β1 plays a pathological role in fibrotic diseases including glomerulosclerosis and renal fibrosis. Smads have been identified as pivotal components in TGF-β intracellular signaling. The present study was carried out to investigate TGF-β1-induced Smad activation in cultured mesangial cells and experimental mesangioproliferative glomerulonephritis in rats. In mesangial cells, TGF-β1, but not BMP-7, induced phosphorylation of Smad2. In contrast, BMP-7, but not TGF-β1, induced phosphorylation of BMP-related Smads. TGF-β1 stimulated the phosphorylation of Smad2 in a dose- and time-dependent manner. Gene transfer using Adenovirus-vector, double-overexpression of Smad2 and Smad4 induced TGF-β1-stimulated plasminogen activator inhibitor-1 (PAI-1) expression more than overexpression of each Smad alone. Furthermore, overexpression of Smad7, one of inhibitory Smads, but not Smd6, blocked TGF-β1-induced PAI-1 expression and reversed TGF-β1-inhibited cell proliferation by inhibiting Smad2 phosphorylation. In experimental glomerulonephritis using Thy-1 nephritis, Smad2 phosphorylation increased transiently and significantly in a similar manner to glomerular matrix expansion. Phosphorylated Smad2 was observed in the damaged glomeruli. These results suggested that Smad proteins are present and act as signaling molecule of TGF-β in mesangial cells in vitro and in vivo. Our results indicate the possibility that modulation of Smad activity may attenuate the development of glomerulosclerosis and fibrosis
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