Oncotarget

Research Papers: Pathology:

Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury

Yi Fang, Hui Zhang, Yihong Zhong and Xiaoqiang Ding _

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Oncotarget. 2016; 7:54317-54328. https://doi.org/10.18632/oncotarget.11104

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Abstract

Yi Fang1,2,3,*, Hui Zhang1,4,*, Yihong Zhong1 and Xiaoqiang Ding1,2,3

1 Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China

2 Shanghai Institute of Kidney and Dialysis, Shanghai, China

3 Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China

4 Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China

* These authors have contributed equally to this work

Correspondence to:

Xiaoqiang Ding, email:

Keywords: prolyl hydroxylase 2; hypoxia inducible factor; renal ischemia-reperfusion injury; autophagy and apoptosis; Pathology Section

Received: June 14, 2016 Accepted: July 19, 2016 Published: August 05, 2016

Abstract

Prolyl hydroxylase domain protein 2 (PHD2) is a key oxygen sensor, setting low steady-state level of hypoxia-inducible factor-α (HIF-α). Here, we showed that treatment of cobalt chloride (CoCl2), a hypoxia mimic, in HK-2 tubular epithelial cells induced PHD2 and HIF-1/2α expression as well as cell apoptosis and autophagy activation. Three methyladenine (3-MA), the autophagy inhibitor, blocked autophagy and protected HK-2 cells from CoCl2. Significantly, siRNA knockdown of PHD2 also protected HK-2 cells from CoCl2,possibly via increasing HIF-1α expression. Reversely, HIF-1α siRNA knockdown almost abolished cytoprotection by PHD2 siRNA in CoCl2-treated HK-2 cells. In vivo, pretreatment with a PHD inhibitor L-mimosine remarkably attenuated mice renal ischemia-reperfusion injuries. Molecularly, L-mimosine inhibited apoptosis and inflammatory responses in injured mice kidneys. Together, our results suggest that PHD2 silence or inhibition protects human renal epithelial cells and mice kidney from hypoxia injuries.


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