Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin : A Possible Role of HIF-1α Expression and Oxygen Metabolism
著者
滝山, 由美
(Takiyama, Yumi)
Harumi, Tatsuo
Watanabe, Jun
Fujita, Yukihiro
Honjo, Jun
Shimizu, Norihiko
Makino, Yuichi
Haneda, Masakazu
上位タイトル
Diabetes
Vol.60,
No.3
(2011.
3)
,p.981-
992
識別番号
ISSN
0012-1797
DOI
10.2337/db10-0655
抄録
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.
