| Item type |
学術雑誌論文 / Journal Article_02(1) |
| 公開日 |
2012-05-17 |
| タイトル |
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タイトル |
Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin : A Possible Role of HIF-1α Expression and Oxygen Metabolism |
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言語 |
en |
| 言語 |
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|
言語 |
eng |
| 資源タイプ |
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資源タイプ |
journal article |
| 著者 |
滝山, 由美
Harumi, Tatsuo
Watanabe, Jun
Fujita, Yukihiro
Honjo, Jun
Shimizu, Norihiko
Makino, Yuichi
Haneda, Masakazu
|
| 書誌情報 |
Diabetes
巻 60,
号 3,
p. 981-992,
発行日 2011-03-01
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| ISSN |
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収録物識別子タイプ |
PISSN |
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収録物識別子 |
0012-1797 |
| DOI |
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関連タイプ |
isVersionOf |
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識別子タイプ |
DOI |
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関連識別子 |
10.2337/db10-0655 |
| 抄録 |
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内容記述タイプ |
Abstract |
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内容記述 |
OBJECTIVE : Chronic hypoxia has been recognized as a key regulator in renal tubulointerstitial fibrosis, as seen in diabetic nephropathy, which is associated with the activation of hypoxia-inducible factor (HIF)-1α. We assess here the effects of the biguanide, metformin, on the expression of HIF-1α in diabetic nephropathy using renal proximal tubular cells and type 2 diabetic rats. RESEARCH DESIGN AND METHODS : We explored the effects of metformin on the expression of HIF-1α using human renal proximal tubular epithelial cells (HRPTECs). Male Zucker diabetic fatty (ZDF; Gmi-fa/fa) rats were treated from 9 to 39 weeks with metformin (250 mg/kg^<−1>/day^<−1>) or insulin. RESULTS : Metformin inhibited hypoxia-induced HIF-1α accumulation and the expression of HIF-1–targeted genes in HRPTECs. Although metformin activated the downstream pathways of AMP-activated protein kinase (AMPK), neither the AMPK activator, AICAR, nor the mTOR inhibitor, rapamycin, suppressed hypoxia-induced HIF-1α expression. In addition, knockdown of AMPK-α did not abolish the inhibitory effects of metformin on HIF-1α expression. The proteasome inhibitor, MG-132, completely eradicated the suppression of hypoxia-induced HIF-1α accumulation by metformin. The inhibitors of mitochondrial respiration similarly suppressed hypoxia-induced HIF-1α expression. Metformin significantly decreased ATP production and oxygen consumption rates, which subsequently led to increased cellular oxygen tension. Finally, metformin, but not insulin, attenuated tubular HIF-1α expression and pimonidazole staining and ameliorated tubular injury in ZDF rats. CONCLUSIONS : Our data suggest that hypoxia-induced HIF-1α accumulation in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxygen consumption. |
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言語 |
en |
| 注記 |
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内容記述タイプ |
Other |
|
注記 |
http://dx.doi.org/10.2337/db10-0655 |
| 資源タイプ |
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内容記述タイプ |
Other |
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資源タイプ |
text |
| 著者版フラグ |
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出版タイプ |
AM |
| フォーマット |
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内容記述タイプ |
Other |
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内容記述 |
application/pdf |
| ID(XooNIps) |
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21282369 |
| 閲覧数(XooNIps) |
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| ダウンロード数(XooNIps) |
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962 |
4490.pdf (1.5 MB)
