Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells
Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells
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DOI：
10.1152/ajprenal.00044.2017
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发表时间：
2018-05-01
影响因子：
4.2
通讯作者：
Agarwal, Anupam
中科院分区：
文献类型：
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作者：
Adedoyin, Oreoluwa;Boddu, Ravindra;Agarwal, Anupam
铁下垂是一种铁依赖的调节性非凋亡性细胞死亡，在急性肾损伤(AKI)模型中造成损害。羟基氧合酶-1(HO-1)是一种细胞保护酶，在细胞应激反应中诱导产生。对AKI有保护作用，因为它具有抗细胞凋亡和抗炎的特性。然而，HO-1在调节铁性下垂中的作用尚不清楚。本研究的目的是阐明HO-1在调节肾近端小管细胞(PTCs)铁链细胞死亡中的作用。从HO-1(+/)(+)和HO-1(-/-)小鼠获得的永生化PTCs在存在或不存在抗氧化剂、铁源或铁络合剂的情况下，用Erastin或RSL3、铁下垂诱导剂进行治疗。评估细胞的形态和代谢活性的变化，作为细胞活力的指标。与赋形剂对照组相比，用erastin处理HO-1(+/+)PTCs后，HO-I基因表达和蛋白水平呈时间和剂量依赖性增加。与HO-1(+/+)PTCs相比，HO1(-/-)细胞表现出剂量依赖性的Erastin或RSL3诱导的细胞死亡增加。与HO-1(+/+)细胞相比，在ERASTIN处理的细胞中补铁柠檬酸铁铵进一步降低了HO-1(-/-)PTCs的细胞存活率。在HO-1(+/+)和HO-1(-/-)PTC中，与铁抑素-1(铁下垂抑制剂)、去铁胺(铁螯合剂)或N-乙酰-L-半胱氨酸(谷胱甘肽补充剂)共同处理均可显著提高细胞存活率，并减弱Erastin诱导的细胞下垂。这些结果证实了HO-1在肾上皮细胞中具有重要的抗铁下垂作用。
Ferroptosis is an iron-dependent form of regulated nonapoptotic cell death, which contributes to damage in models of acute kidney injury (AKI). Herne oxygenase-1 (HO-1) is a cytoprotective enzyme induced in response to cellular stress. and is protective against AKI because of its antiapoptotic and anti-inflammatory properties. However, the role of HO-1 in regulating ferroptosis is unclear. The purpose of this study was to elucidate the role of HO-1 in regulating ferroptotic cell death in renal proximal tubule cells (PTCs). Immortalized PTCs obtained from HO-1(+/)(+) and HO-1(-/-) mice were treated with erastin or RSL3, ferroptosis inducers, in the presence or absence of antioxidants, an iron source, or an iron chelator. Cells were assessed for changes in morphology and metabolic activity as an indicator of cell viability. Treatment of HO-1(+/+) PTCs with erastin resulted in a time- and dose-dependent increase in HO-i gene expression and protein levels compared with vehicle-treated controls. HO1(-/-) cells showed increased dose-dependent erastin- or RSL3-induced cell death in comparison to HO-1(+/+) PTCs. Iron supplementation with ferric ammonium citrate in erastin-treated cells decreased cell viability further in HO-1(-/-) PTCs compared with HO-1(+/+) cells. Cotreatment with ferrostatin-1 (ferroptosis inhibitor), deferoxamine (iron chelator), or N-acetyl-L-cysteine (glutathione replenisher) significantly increased cell viability and attenuated erastin-induced fer roptosis in both HO-1(+/+) and HO-1(-/-) PTCs. These results demon strate an important antiferroptotic role of HO-1 in renal epithelial cells.