Protective role of AMP-activated protein kinase-evoked autophagy on an in vitro model of ischemia/reperfusion-induced renal tubular cell injury.
Protective role of AMP-activated protein kinase-evoked autophagy on an in vitro model of ischemia/reperfusion-induced renal tubular cell injury.
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DOI：
10.1371/journal.pone.0079814
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hwa Liu S
中科院分区：
文献类型：
--
作者：
Wang LT;Chen BL;Wu CT;Huang KH;Chiang CK;Hwa Liu S
缺血/再灌注（I/R）损伤是靶器官如脑、心脏和肾脏损伤的常见原因。I/R引起的肾损伤可能发生在肾移植、手术、创伤或脓毒症中，已知是急性肾损伤的重要原因。肾I/R损伤的分子机制尚不完全清楚。在这里，我们研究的作用，AMP激活的蛋白激酶（AMPK）诱导的自噬在肾近端小管细胞死亡在体外I/R损伤模型。为了模拟体内肾I/R损伤，LLC-PK 1细胞，一种来自猪肾的肾小管细胞系，用抗霉素A和2-脱氧葡萄糖处理以模拟缺血损伤，然后用生长培养基再灌注。该I/R损伤模型以时间依赖性方式显著诱导LLC-PK 1细胞凋亡和自噬。自噬抑制剂3-甲基腺嘌呤（3 MA）显著增强I/R损伤诱导的细胞凋亡。I/R还可上调AMPK的磷酸化，下调mTOR的磷酸化。AMPK的小发夹RNA（shRNA）转染的细胞在I/R期间显著增加mTOR的磷酸化以及减少自噬的诱导，随后增强细胞凋亡。此外，mTOR抑制剂RAD 001在I/R期间显著增强自噬并减弱细胞凋亡。总之，这些发现表明，自噬诱导通过AMPK调节的mTOR通路在体外I/R损伤模型中保护肾小管细胞损伤。AMPK诱导的自噬可能成为I/R肾损伤治疗的潜在靶点。
Ischemia/reperfusion (I/R) injury is a common cause of injury to target organs such as brain, heart, and kidneys. Renal injury from I/R, which may occur in renal transplantation, surgery, trauma, or sepsis, is known to be an important cause of acute kidney injury. The detailed molecular mechanism of renal I/R injury is still not fully clear. Here, we investigate the role of AMP-activated protein kinase (AMPK)-evoked autophagy in the renal proximal tubular cell death in an in vitro I/R injury model. To mimic in vivo renal I/R injury, LLC-PK1 cells, a renal tubular cell line derived from pig kidney, were treated with antimycin A and 2-deoxyglucose to mimic ischemia injury followed by reperfusion with growth medium. This I/R injury model markedly induced apoptosis and autophagy in LLC-PK1 cells in a time-dependent manner. Autophagy inhibitor 3-methyladenine (3MA) significantly enhanced I/R injury-induced apoptosis. I/R could also up-regulate the phosphorylation of AMPK and down-regulate the phosphorylation of mammalian target of rapamycin (mTOR). Cells transfected with small hairpin RNA (shRNA) for AMPK significantly increased the phosphorylation of mTOR as well as decreased the induction of autophagy followed by enhancing cell apoptosis during I/R. Moreover, the mTOR inhibitor RAD001 significantly enhanced autophagy and attenuated cell apoptosis during I/R. Taken together, these findings suggest that autophagy induction protects renal tubular cell injury via an AMPK-regulated mTOR pathway in an in vitro I/R injury model. AMPK-evoked autophagy may be as a potential target for therapeutic intervention in I/R renal injury.
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影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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