| Project/Area Number |
10670985
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | The University of Tokyo School of Medicine (Branch Hospital) |
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Principal Investigator |
KANAME Shinya University of Tokyo School of Medicine (Branch Hospital), The Department of Internal Medicine, Assistant Professor, 医学部・附属病院・分院, 助手 (60224581)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | stretch / mesangial cells / TGF-β / LTBP / glomerulosclerosis / glomerular hypertension / extracellular matrix / LOX-1 |
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| Research Abstract |
In glomerular hypertension mesangial cells are believed to perceive the increased cyclic strain and we have recently reported that cyclic mechanical stretch in vitro enhances the expression of ECM components via an autocrine/paracrine secretion of TGF-β in cultured rat mesangial cells. TGF-β is usually secreted as a large latent complex associated with latent TGF-β binding protein-1 (LTBP-1), which is known to bind to extracellular matrix (ECM) components. Because the LTBP-ECM interaction has been suggested to play a role in the activation and biological action of TGF-β, we examined the role of LTBP-1 in the stretch-induced, TGF-β mediated ECM expression. Mesangial cells expressed mRNA for short and long forms of LTBP-1, LTBP-1S and LTBP-1L, respectively. Mesangial cells were subjected to cyclic stretch for 24-36 h in the presence of polyclonal antibody raised against human LTBP-1 or synthetic oligopeptides corresponding to N-terminal portions of human LTBP-1, which is to work as competitive inhibitors against the LTBP-ECM association. Both anti-LTBP-1 antibody and synthetic oligopeptides inhibited the stretch-induced mRNA expression of type I collagen and fibronectin in a dose-dependent manner, but the inhibition by Ab39 and the oligopeptides was recovered by adding recombinant TGF-β Ab39 or the oligopeptides did not change the effect of exogenously added TGF-β such as growth inhibition in mink lung epithelial cells. These results suggest that mesangial cells secrete TGF-β as large latent complex and the LTBP-ECM interaction may be a pivotal step in TGF-β action and ECM accumulation, providing a new therapeutic strategy against progression of glomerulosclerosis and other fibrotic diseases.
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