Participation of autophagy in renal ischemia/reperfusion injury
Participation of autophagy in renal ischemia/reperfusion injury
复制标题
DOI：
10.1016/j.bbrc.2008.01.059
复制
发表时间：
2008-03-28
影响因子：
3.1
通讯作者：
Iniai, Enyu
中科院分区：
文献类型：
--
作者：
Suzuki, Chigure;Isaka, Yoshitaka;Iniai, Enyu
肾缺血再灌注（I/R）损伤是移植过程中不可避免的，它导致肾小管上皮细胞死亡。我们观察到I/ r损伤小鼠模型和人移植肾活检标本的小管上皮细胞中自噬体的增加。然而，目前尚不清楚自噬是否作为一种保护途径发挥作用，或者是否有助于I/ r诱导的细胞死亡。本研究以人肾近端小管上皮细胞系HK-2为研究对象，探讨低氧（1% O-2）或活性氧（500 μ M H2O2）激活下自噬的作用。与常氧条件相比，48小时的缺氧轻度增加lc3标记的自噬空泡，并显著增加lamp2标记的溶酶体。我们在小鼠ir损伤模型中观察到类似的变化。然后，我们通过使用溶酶体蛋白酶抑制剂抑制自噬液泡的下游溶酶体降解来评估自噬的产生和降解。我们发现，在溶酶体蛋白酶抑制剂存在的低氧条件下，自噬体显著增加，这表明低氧诱导自噬产生和降解的高周转率。此外，自噬抑制显著抑制h2o2诱导的细胞死亡。综上所述，自噬的高周转率可能导致I/R损伤时自噬细胞死亡。(C) 2008爱思唯尔公司版权所有。
Renal ischemia reperfusion (I/R) injury is inevitable in transplantation, and it results in renal tubular epithelial cells undergoing cell death. We observed an increase in autophagosomes in the tubular epithelial cells of I/R-injured mouse models, and in biopsy specimens from human transplanted kidney. However, it remains unclear whether autophagy functions as a protective pathway, or contributes to I/R-induced cell death. Here, we employed the human renal proximal tubular epithelial cell line HK-2 in order to explore the role of autophagy under hypoxia (1% O-2) or activation of reactive oxygen species (500 mu M H2O2). When compared to normoxic conditions, 48 h of hypoxia slightly increased LC3-labeled autophagic vacuoles and markedly increased LAMP2-labeled lysosomes. We observed similar changes in the mouse IR-injury model. We then assessed autophagic generation and degradation by inhibiting the downstream lysosomal degradation of autophagic vacuoles using lysosomal protease inhibitor. We found that autophagosomes increased markedly under hypoxia in the presence of lysosomal protease inhibitors, thus suggesting that hypoxia induces high turnover of autophagic generation and degradation. Furthermore, inhibition of autophagy significantly inhibited H2O2-induced cell death. In conclusion, high turnover of autophagy may lead to autophagic cell death during I/R injury. (C) 2008 Elsevier Inc. All rights reserved.