Bcl-2 Protects Tubular Epithelial Cells From Ischemia/Reperfusion Injury by Dual Mechanisms
Bcl-2 Protects Tubular Epithelial Cells From Ischemia/Reperfusion Injury by Dual Mechanisms
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DOI：
10.1016/j.transproceed.2008.10.026
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发表时间：
2009-01-01
影响因子：
0.9
通讯作者：
Takahara, S.
中科院分区：
文献类型：
--
作者：
Isaka, Y.;Suzuki, C.;Takahara, S.
肾移植后移植肾功能延迟与肾缺血再灌注(I/R)损伤引起的肾小管上皮细胞广泛丢失有关。最近的报道表明，I/R损伤导致的细胞死亡是通过自噬发生的，这是一种细胞降解过程，负责不必要的或功能失调的细胞器和细胞质蛋白的周转，以及细胞凋亡。最近，我们发现抗凋亡因子Bcl2的过表达抑制了肾小管细胞的凋亡和随后的肾小管间质损伤。在几种疾病的细胞死亡过程中也可以观察到自噬。因此，我们推测，增加的Bcl2蛋白可能通过抑制自噬和抑制凋亡来保护肾小管上皮细胞。本研究利用自噬小体标记Lc3-GFP的转基因小鼠模型(Lc3-GFP TG)和Bcl2/Lc3-GFP双转基因小鼠(Bcl2/Lc3-GFP Tg)，研究了Bcl2对缺血再灌注诱导的自噬的影响。I/R损伤伴随着正常肾小管形态的显著破坏，促进了Lc3-GFP点的形成，代表了广泛诱导的自噬小体。在电子显微镜下，I/R损伤的肾小管上皮细胞的自噬小体中含有线粒体。相反，Bcl2的增强抑制了自噬小体的形成，对肾小管的损伤较小。结论：Bcl2增强通过抑制自噬降解和抑制肾小管上皮细胞凋亡来保护肾小管上皮细胞免受I/R损伤。
Ischemia/reperfusion (I/R) injury, which induces extensive loss of tubular epithelial cells, is associated with delayed graft function following kidney transplantation. Recent reports have suggested that cell death by I/R injury occurs by autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, as well as by apoptosis. Recently, we demonstrated that overexpression of the anti-apoptotic factor, Bcl-2, inhibited tubular apoptosis and subsequent tubulointerstitial damage after I/R injury. Autophagy is also observed in cells undergoing cell death in several diseases. Therefore, we hypothesized that increased Bcl-2 protein may protect tubular epithelial cells by suppressing autophagy and inhibiting apoptosis. In the present study, a transgenic mouse model (LC3-GFP TG) in which autophagosomes are labeled with LC3-GFP and Bcl-2/LC3-GFP double transgenic mice (Bcl-2/LC3-GFP TG) were used to examine the effect of Bcl-2 on I/R-induced autophagy. I/R injury, which is associated with marked disruption of normal tubular morphology, promoted the formation of LC3-GFP dots, representing extensively induced autophagosomes. On electron microscopy, the autophagosomes contained mitochondria in I/R-injured tubular epithelial cells. In contrast, Bcl-2 augmentation suppressed the formation of autophagosomes and there was less tubular damage. In conclusion, Bcl-2 augmentation protected renal tubular epithelial cells from I/R injury by suppressing autophagosomal degradation and inhibiting tubular apoptosis.