| Project/Area Number |
17590925
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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 |
Metabolomics
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| Research Institution | Kanazawa Medical University |
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Principal Investigator |
KOYA Daisuke Kanazawa Medical University, Professor, 医学部, 教授 (70242980)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | kidney diseaes / sitr1 / apoptosis / oxidative stress / TGF-beta / smad 7 / 酸化ストレス / H2O2 |
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| Research Abstract |
Oxidative stress and/or TGF-beta-induced apoptosis of renal glomerular cells is an important factor for the development of various kidney diseases. Identification of molecules that modulate this process could lead to the development of new strategies for preventing kidney diseases. In this study, we evaluated whether mammalian silent information regulator 2 (SIRT1), which has been recently identified as a cell survival factor countering various stressors, is a key regulator of oxidative stress-induced mesangial cell apoptosis. Morphological features of apoptotic cell death (nuclear condensation) and the expression of biochemical pro-apoptotic markers [cleavages of caspase-3 and poly (ADP-ribose) polymerase (PARP)] were assessed in murine mesangial cells (MMC_s) exposed to hydrogen peroxide (H_2O_2) or TGF-beta. H_2O_2 or TGF-beta increased mesangial cell apoptosis, predominantly through p53 activation by acetylation, which is a post-transcriptional modification for p53 activation. H_2O
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_2 or TGF-beta-induced apoptosis was significantly attenuated in SIRT1-overexpressing MMCs, but enhanced in SIRT1-knockdown MMCs. We also find that SIRT1 directly interacts with the N-terminus of Smad7. Furthermore, SIRT1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (K64 and K70) on Smad7. In vivo, levels of Smad7 protein expression was reduced by SIRT1-overexpression and increased by SIRT 1-knockdown via modulating smurfl-mediated Smad7 degradation via ubiquitin proteasome action. Our results indicate that SIRT1 can prevent oxidative stress-induced apoptosis through p53 inactivation in mesangial cells and Smad7 is a new target molecule for SIRT1, and functionally SIRT1 attenuates TGFβ-induced vascular cell apoptosis through acceleration of Smad7 degradation. Up-regulation of SIRT1 may provide a new strategy for preventing kidney glomerular diseases. We next examine the target molecules which have the ability to induce SIRT1 by using a protein chip analysis and find that 24 candidates specific to calorie resariction. Less
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