| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1997: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1996: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
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| Research Abstract |
The aim of this study is to clarify the role of tubular epithelial cells in the pathogenesis of renal interstitial fibrosis. First of all, we investigated the expression of proliferating cell nuclear antigen (PCNA), osteopontin (OPN), alpha-smooth muscle actin (SMA), and macrophage cell marker (ED-1) in unilateral obstruction (UUO)-treated rat kidney using immunohistochemical technique. The results showed that PCNA positive cells dramatically increased within 3 days after operation and gradually decreased by 2 weeks. PCNA positive cells were mainly tubular epithelial cells in early stage of this model. However interstitial cells became positive for PCNA after 4 weeks from operation. Expression of OPN in proximal tubular epithelial cells and infiltration of ED-1 positive cells were also increased until 5 days after operation. alpha-SMA positive cells were gradually increased after 7 days. Interstitial volume that was evaluated by point counting method in the kidney of UUO model apparent
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ly increased after 2 weeks. Using this animal model, we administrated mizoribin that is a kind of immunosuppresive agents for 5 days immediately after operation, and then evaluated histological parameters after 7 days from operation. Animals treated with mizoribin showed significant reduction of infiltrating cells in the renal interstitium, in spit of the similar expression of OPN in the proximal tubular epithelial cells. The interstitial volume of the kidney in the treated animal also dramatically reduced compared with that in non-treated animal. These data indicate that infiltration of mononuclear cells into the interstitium was always followed by interstitial fibrosis in this model. Then we decided to investigate the effects of physical force on cellular behavior of tubular epithelial cells. Human proximal tubular epithelial cells were cultured on fibronectine-coated silicon rubber, and then 20 % of static-stretch was employed to induce physical force. Concentration of TGF-beta, IL-1, and MCP-1 in culture supernatants were measured using ELISA at 24 and 48 hours after initiation of static stretch and compared with non-stretch condition. After 24hrs, the concentration of TGF-beta in the supernatant of the static-stretch group showed higher level than that of non-stretch culture supernatant. After 48hrs, IL-1 and MCP-1 level of culture supernatant were also increased in the static-stretch group compared with non-stretch culture supernatant. Our results indicate that the physical force evokes the production of cytokines and chemokines from tubular epithelial cells, and that these molecules are responsible for mononuclear cell infiltration. From these observations, we concluded that tubular epithelial cells have important roles for fibrogenesis of renal interstitium in this model. Less
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