title: Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury.
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.
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Institute of Kidney and Dialysis, Shanghai, China.|Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Institute of Kidney and Dialysis, Shanghai, China.|Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology; D019610:Cytoprotection; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000502:physiology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D051379:Mice; D008898:Mimosine / Q000627:therapeutic use*; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D064800:Prolyl-Hydroxylase Inhibitors; D003035:Cobalt; D008898:Mimosine; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C018021:cobaltous chloride
keywords: Pathology Section; autophagy and apoptosis; hypoxia inducible factor; renal ischemia-reperfusion injury; prolyl hydroxylase 2