| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
Renal interstitial fibrosis in mice is caused by unilateral urethral obstruction (UUO). TGF-b is reportedly upregulated in renal tubular epithelial cells in response to injurious stimuli of UUO, causing renal fibrosis associated with epithelial-mesenchymal transition (EMT). We demonstrated using Smad3 knockout mice that Smad3 pathway is central to the pathogenesis of interstitial fibrosis via EMT of renal tubular epithelial cells. In this study, we sought to elucidate the molecular interaction between Smad3 and other molecules in renal tubular epithelial cells when they transform to mesenchymal cells. We generated the transgenic mice that overexpress Smad3 under a CMV promoter, in which lens epithelial cells spontaneously transform to mesenchymal cell about 10 weeks after birth, resulting in cataract. In addition, in a experiment of UUO using TNF-a KO mice, the degree of renal interstitial fibrosis increased in 4 weeks after UUO, whereas no obvious difference was observed between KO and wild-type mice. In the KO kidneys, the expression of Snail, a key molecule for EMT, was elevated, concomitant with the increase of Coll and aSMA. Also, in the experiments using adenoviral gene transfer of Smad7, Bmp7, Id2, and Id3, the corneal wound healing was accelerated and EMT in lens epithelial cells was suppressed. These adenoviral gene transfers are also applied to UUO experiments to examine whether the levels of renal fibrosis can be suppressed.
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