Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin

Abstract

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.

DOI: 10.2337/db10-0655

Extracted Key Phrases

8 Figures and Tables

01002002011201220132014201520162017
Citations per Year

482 Citations

Semantic Scholar estimates that this publication has 482 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Takiyama2011TubularII, title={Tubular Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin}, author={Yumi Takiyama and Tatsuo Harumi and Jun Watanabe and Yukihiro Fujita and Jun Honjo and Norihiko Shimizu and Yuichi Makino and Masakazu Haneda}, booktitle={Diabetes}, year={2011} }