Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury.
Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury.
复制标题
DOI：
10.18632/oncotarget.11104
复制
发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Fang Y;Zhang H;Zhong Y;Ding X
脯氨酰羟化酶结构域蛋白2（Prolyl hydroxylase domain protein 2，PHD 2）是一种重要的氧传感器，调节低氧诱导因子-α（hypoxia-inducible factor-α，HIF-α）的稳态水平。在此，我们发现氯化钴（CoCl 2），一种低氧模拟物，在HK-2肾小管上皮细胞中诱导PHD 2和HIF-1/2α表达以及细胞凋亡和自噬激活。三甲基腺嘌呤（3-MA），自噬抑制剂，阻断自噬和保护HK-2细胞从氯化钴。值得注意的是，siRNA敲低PHD 2也保护HK-2细胞免受CoCl 2的影响，可能是通过增加HIF-1α表达。然而，HIF-1α siRNA敲低几乎取消了CoCl 2处理的HK-2细胞中PHD 2 siRNA的细胞保护作用。在体内，PHD抑制剂L-含羞草碱预处理可显著减轻小鼠肾缺血再灌注损伤。在分子水平上，L-含羞草碱抑制损伤小鼠肾脏的细胞凋亡和炎症反应。总之，我们的研究结果表明，PHD 2沉默或抑制保护人肾上皮细胞和小鼠肾脏免受缺氧损伤。
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.