Autophagy Guards Against Cisplatin-Induced Acute Kidney Injury
Autophagy Guards Against Cisplatin-Induced Acute Kidney Injury
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DOI：
10.1016/j.ajpath.2011.11.001
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发表时间：
2012-02-01
影响因子：
6
通讯作者：
Rakugi, Hiromi
中科院分区：
文献类型：
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作者：
Takahashi, Atsushi;Kimura, Tomonori;Rakugi, Hiromi
自噬是一种高度保守的蛋白质降解途径，参与细胞内环境的稳定。虽然新出现的证据表明自噬参与各种条件下，努力澄清自噬在肾小管中的作用正在开始阐明。在本研究中，我们研究了自噬通过使用顺铂诱导的AM模型调节导致肾小管细胞死亡的几种恶化途径来预防急性肾损伤（阿基）的假设。顺铂处理GFP-LC 3（绿色荧光蛋白微管相关蛋白1轻链3）转基因小鼠以时间依赖性方式诱导肾脏近端小管中的自噬。近端小管特异性自噬缺陷小鼠表现出更严重的顺铂诱导的AM比对照组小鼠，通过肾功能和形态学结果进行评估。此外，顺铂诱导更严重的DNA损伤和p53激活，伴随着凋亡细胞数量的增加，以及自噬缺陷近端小管中蛋白质聚集体的大量积累。顺铂治疗显着增加活性氧产生损伤的线粒体在永生化的自噬缺陷的近端肾小管细胞相比，自噬恢复的控制细胞。总之，自噬可能通过减轻DNA损伤和活性氧的产生以及消除有毒蛋白质聚集体来保护肾近端小管免受AM的侵害。增强自噬可能提供一种新的治疗选择，以尽量减少MU。(Am J Pathol 2012，180：517-525; DOI：10.1016/j.path.2011.11.001）
Autophagy is a highly conserved bulk protein degradation pathway involved in cellular homeostasis. Although emerging evidence indicates involvement of autophagy in various conditions, efforts to clarify the role of autophagy in renal tubules are beginning to be elucidated. In the present study, we examined the hypothesis that autophagy guards against acute kidney injury (AKI) by modulating several deteriorative pathways that lead to tubular cell death using a cisplatin-induced model of AM. Cisplatin treatment of GFP-LC3 (green fluorescent protein microtubule-associated protein 1 light chain 3) transgenic mice induced autophagy in kidney proximal tubules in a time-dependent manner. Proximal tubule specific autophagy-deficient mice exhibited more severe cisplatin-induced AM than did control mice, as assessed via kidney function and morphologic findings. In addition, cisplatin induced more severe DNA damage and p53 activation, concomitant with an increase in apoptotic cell number, and a massive accumulation of protein aggregates in autophagy-deficient proximal tubules. Cisplatin treatment significantly increased reactive oxygen species producing damaged mitochondria in immortalized autophagy-deficient proximal tubular cells when compared with autophagy-retrieved control cells. In conclusion, autophagy guards kidney proximal tubules against AM, possibly by alleviating DNA damage and reactive oxygen species production and by eliminating toxic protein aggregates. Enhancing autophagy may provide a novel therapeutic option to minimize MU. (Am J Pathol 2012, 180:517-525; DOI: 10.1016/j.path.2011.11.001)