Cardiovascular , Pulmonary , and Renal Pathology Autophagy Guards Against Cisplatin-Induced Acute Kidney Injury
Cardiovascular , Pulmonary , and Renal Pathology Autophagy Guards Against Cisplatin-Induced Acute Kidney Injury
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发表时间：
2012
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通讯作者：
Atsushi Takahashi;Tomonori Kimura;Yoshitsugu Takabatake;T. Namba;J. Kaimori;Harumi Kitamura;I. Matsui-I.-Ma
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作者：
Atsushi Takahashi;Tomonori Kimura;Yoshitsugu Takabatake;T. Namba;J. Kaimori;Harumi Kitamura;I. Matsui-I.-Ma
自噬是一种高度保守的大量蛋白质降解途径，参与细胞稳态。尽管新出现的证据表明自噬参与各种情况，但澄清自噬在肾小管中的作用的努力已开始得到阐明。在本研究中，我们使用顺铂诱导的 AKI 模型检验了自噬通过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 (AKI) 的假设。顺铂处理 GFP-LC3（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近端小管自噬。根据肾功能和形态学结果评估，近端小管特异性自噬缺陷小鼠比对照小鼠表现出更严重的顺铂诱导的 AKI。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，以及自噬缺陷的近端小管中蛋白质聚集体的大量积累。与自噬修复的对照细胞相比，顺铂治疗显着增加了永生化自噬缺陷的近端肾小管细胞中活性氧的产生，从而产生受损的线粒体。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物来保护肾脏近曲小管免受 AKI 的影响。增强自噬可能提供一种新的治疗选择，以最大限度地减少 AKI。 （Am J Pathol 2012 年，180：517–525；DOI：10.1016/j.ajpath.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 AKI. 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 AKI 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 autophagyretrieved control cells. In conclusion, autophagy guards kidney proximal tubules against AKI, 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 AKI. (Am J Pathol 2012, 180:517–525; DOI: 10.1016/j.ajpath.2011.11.001)