2002 Fiscal Year Final Research Report Summary
Development of the treatment of diabetic nephropathy by targeting the TGF-β signaling
| Project/Area Number |
12470227
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
KIKKAWA Ryuichi Shiga Univ.of Medical Science President, 医学部, 学長 (50093406)
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| Co-Investigator(Kenkyū-buntansha) |
KOYA Daisuke Shiga University of Medical Science, Assistant Professor, 医学部, 助手 (70242980)
HANEDA Masakazu Shiga University of Medical Science, Associate Professor, 医学部, 講師 (60164894)
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| Project Period (FY) |
2000 – 2002
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| Keywords | mesangial cells / TGF-β / Smad / Ac-SDKP / pioglitazone / fibronectin / AP-1 |
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| Research Abstract |
Diabetic nephropathy is characterized by an accumulation of extracellular matrix (ECM) proteins. TGF-β is a key cytokine which mediates the progression of diabetic nephropathy. In this study, we examined the intracellular mechanism by which TGF-β-induced ECM proteins such as fibronectin, one of the major ECM proteins accumulated in renal glumeruli. We also examined the effects of pioglitazone, new insulin sensitizing agent, and N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) which was increased by the treatment of angiotensin converting enzyme inhibitors on TGF-β-induced ECM expression and intracellular signaling pathways. In cultured mesangial cells, TGF-β1 stimulated nuclear translocation of Smad2, 3, 4 and activated ERK and JNK. TGF-β1 induced fibronectin mRNA expression, and this was inhibited by a specific MEK inhibitor, PD98059 without affecting Smad signaling. These results suggest that MEK-ERK pathway is required for TGF-β-induced fibronectin expression. Pioglitazone inhibited TGF-β1-induced fibronectin expression by inhibiting TGF-β-inducedAP-1 but not ERK activation. Ac-SDKP inhibited TGF-β-induced PAI-1 and type I collagen expressions. Ac-SDKP inhibited activation of Smad2, 3 and SBE reporter activity by TGF-β1. The overexpressed Smad7 was translocated from the nucleus to the cytosol by Ac-SDKP, suggesting that Ac-SDKP inhibited Smad signaling via Smad7 translocation. These results provide novel evidence that pioglitazone and Ac-SDKP has an antifibrotic effect, and inhibiting the TGF-β signaling by these agents could be a useful therapy to diabetic nephropathy.
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