Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells.
Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells.
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DOI：
10.1111/tri.12465
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Jani A
中科院分区：
文献类型：
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作者：
Jain S;Keys D;Nydam T;Plenter RJ;Edelstein CL;Jani A
肾脏长期冷藏和复温（CS/REW）是移植肾功能延迟恢复（DGF）的危险因素。对肾小管上皮细胞（RTEC）的研究已经确定了单独冷藏（CS）或复温模型中的细胞凋亡和自噬。在RTECS中，冷藏和复温对细胞凋亡和自噬的影响尚不清楚，并且与DGF相关，因为肾脏经受CS和复温。我们假设RTECs的CS/REW会诱导自噬，从而防止细胞凋亡。在CS/REW中，RTEC的自噬通量增加。在CS/REW期间，使用Atg 5 siRNA的自噬抑制导致裂解的胱天蛋白酶-3增加和凋亡细胞增加（在形态学和膜联蛋白V染色上）。自噬抑制对RTEC中坏死的影响尚不清楚。在CS/REW期间，坏死和caspase-1（坏死的介质）增加，Atg 5 siRNA对坏死和caspase-1没有影响。在肾移植模型中，在冷藏后移植的肾脏中，自噬的标志物LC 3 II增加。总之，自噬通量在CS/REW期间增加。在CS/REW期间，自噬抑制导致裂解的caspase-3增加和凋亡增加，而对坏死或caspase-1没有影响。总之，CS/REW后RTEC中的自噬抑制诱导凋亡性细胞死亡，并且作为减少DGF的疗法可能是有害的。
Prolonged cold storage and re-warming (CS/REW) of kidneys are risk factors for delayed graft function (DGF). Studies in renal tubular epithelial cells (RTECs) have determined apoptosis and autophagy in models of either cold storage (CS) or re-warming alone. The effect of both cold storage and re-warming on apoptosis and autophagy, in RTECS is not known and is relevant to DGF as the kidney is subjected to both CS and re-warming. We hypothesized that CS/REW of RTECs would induce autophagy that protects against apoptosis. In CS/REW, there was increased autophagic flux of RTECs. Autophagy inhibition using an Atg5 siRNA resulted in increased cleaved caspase-3 and increased apoptotic cells (on both morphology and annexin V staining) during CS/REW. The effect of autophagy inhibition on necrosis in RTECs is unknown. There were increased necrosis and caspase-1, a mediator of necrosis, during CS/REW, and the Atg5 siRNA had no effect on necrosis and caspase-1. In a kidney transplant model, there was an increase in LC3 II, a marker of autophagy, in kidneys transplanted after cold storage. In summary, autophagic flux is increased during CS/REW. Autophagy inhibition resulted in increased cleaved caspase-3 and increased apoptosis during CS/REW without an effect on necrosis or caspase-1. In conclusion, autophagy inhibition in RTECs after CS/REW induces apoptotic cell death and may be deleterious as a therapy to decrease DGF.