Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.
Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.
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DOI：
10.1371/journal.pone.0140025
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kaushal GP
中科院分区：
文献类型：
--
作者：
Chandrika BB;Yang C;Ou Y;Feng X;Muhoza D;Holmes AF;Theus S;Deshmukh S;Haun RS;Kaushal GP
我们研究了内质网（ER）应激诱导的自噬是否提供细胞保护作用，防止氧化剂和化学缺氧引起的体外肾小管上皮细胞损伤，以及体内缺血再灌注（IR）损伤。我们证明，ER应激诱导剂衣霉素触发未折叠的蛋白质反应，上调ER伴侣Grp 78，并激活培养的肾小管上皮细胞中的自噬途径。抑制ER应激诱导的自噬加速了caspase-3的激活和细胞死亡，这表明ER应激诱导的自噬具有促生存作用。与野生型细胞相比，自噬缺陷的MEFs经历ER应激增强了caspase-3活化和细胞死亡，这一发现进一步支持了ER应激诱导的自噬的细胞保护作用。内质网应激诱导的自噬对氧化剂H2 O2和叔丁基过氧化氢以及抗霉素A诱导的化学缺氧具有明显的细胞保护作用。相反，抑制ER应激诱导的自噬或自噬缺陷细胞显着增强细胞死亡的氧化损伤和化学缺氧。在小鼠肾脏中，类似于培养的肾上皮细胞，衣霉素触发ER应激，显著上调Grp 78，并激活自噬而不损害自噬通量。此外，ER应激诱导的自噬显著改善了肾IR损伤，这从肾功能和组织学的显著改善中可见一斑。氯喹抑制自噬显着增加肾脏IR损伤。这些研究强调了ER应激诱导的自噬在体外和体内肾缺血再灌注损伤中的有益影响。
We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.