Autophagy in proximal tubules protects against acute kidney injury.
Autophagy in proximal tubules protects against acute kidney injury.
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DOI：
10.1038/ki.2012.261
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发表时间：
2012-12
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
自噬在急性肾损伤中诱导肾小管细胞发生，然而，这是保护性的还是损伤性的仍然存在争议。我们使用顺铂和缺血再灌注诱导的急性肾损伤的小鼠模型，通过药理学和遗传学阻断自噬来解决这个问题。氯喹是一种自噬的药理学抑制剂，在两种模型中均可阻断自噬通量并增强急性肾损伤。然而，雷帕霉素激活自噬并保护免受顺铂诱导的急性肾损伤。我们还建立了一个肾近端小管特异性自噬相关基因7敲除小鼠模型，该模型在基础和顺铂诱导的肾脏自噬中均存在缺陷。与野生型同窝小鼠相比，这些基因敲除小鼠对顺铂诱导的急性肾损伤明显更敏感，如肾功能丧失、组织损伤和细胞凋亡所示。从机制上讲，这些基因敲除小鼠增强了p53和c-Jun N末端激酶的激活，这是导致顺铂急性肾损伤的信号通路。从基因敲除小鼠分离的近端肾小管细胞对顺铂诱导的凋亡比野生型小鼠的细胞更敏感。此外，基因敲除小鼠对肾缺血再灌注损伤比野生型小鼠更敏感。因此，我们的研究结果建立了肾小管细胞自噬在急性肾损伤中的肾保护作用，它可能会干扰细胞杀伤机制。
Autophagy is induced in renal tubular cells during acute kidney injury, however, whether this is protective or injurious remains controversial. We address this question by pharmacologic and genetic blockade of autophagy using mouse models of cisplatin- and ischemia-reperfusion induced acute kidney injury. Chloroquine, a pharmacological inhibitor of autophagy, blocked autophagic flux and enhanced acute kidney injury in both models. Rapamycin, however, activated autophagy and protected against cisplatin-induced acute kidney injury. We also established a renal proximal tubule-specific autophagy-related gene 7 knockout mouse model shown to be defective in both basal and cisplatin induced autophagy in kidneys. Compared with wild-type littermates, these knockout mice were markedly more sensitive to cisplatin-induced acute kidney injury as indicated by renal functional loss, tissue damage, and apoptosis. Mechanistically, these knockout mice had heightened activation of p53 and c-Jun N terminal kinase, signaling pathways contributing to cisplatin acute kidney injury. Proximal tubular cells isolated from the knockout mice were more sensitive to cisplatin-induced apoptosis than cells from wild-type mice. In addition, the knockout mice were more sensitive to renal ischemia-reperfusion injury than their wild-type littermates. Thus, our results establish a renoprotective role of tubular cell autophagy in acute kidney injury where it may interfere with cell killing mechanisms.
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影响因子：
8
作者：
Jiang, M.;Wei, Q.;Dong, Z.
通讯作者：
Dong, Z.
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
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影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
6.1
作者：
Bardag-Gorce, F;Francis, T;French, SW
通讯作者：
French, SW
影响因子：
3.9
作者：
Fujishima, Yoshimi;Nishiumi, Shin;Yoshida, Masaru
通讯作者：
Yoshida, Masaru