Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury.
Loss of DEPTOR in renal tubules protects against cisplatin-induced acute kidney injury.
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肾小管中 DEPTOR 的缺失可预防顺铂引起的急性肾损伤
DOI：
10.1038/s41419-018-0483-3
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Wang C;Dai H;Xiong Z;Song Q;Zou Z;Li M;Nie J;Bai X;Chen Z
含DEP结构域的mTOR相互作用蛋白（DEPTOR）最初被鉴定为雷帕霉素机制靶点（mTOR）的体内双重抑制剂。最近报道，它在体外参与肾脏生理和病理;然而，其在体内的详细作用和机制是完全未知的。我们观察到顺铂治疗后第3天肾脏中的DEPTOR表达显著增加，此时细胞凋亡达到峰值，表明DEPTOR与顺铂诱导的急性肾损伤（阿基）有关。然后，我们使用Cre-LoxP系统产生突变小鼠，其中DEPTOR基因在近端小管细胞中特异性缺失。DEPTOR缺乏没有改变生理盐水处理组的肾组织学或功能，表明在生理条件下DEPTOR对肾功能不是必需的。有趣的是，在顺铂治疗后，DEPTOR缺失广泛地保留了肾组织学并维持了肾功能，这表明DEPTOR的缺失改善了顺铂诱导的阿基。在机制上，DEPTOR在体内和体外调节p38 MAPK信号传导和TNFα产生，而不是mTOR信号传导，从而缓和顺铂诱导的炎症反应和细胞凋亡。总的来说，我们的研究结果证明了DEPTOR在肾脏生理学和病理学调节中的作用和机制，并证明了近端小管中DEPTOR的丢失可以防止顺铂诱导的阿基。
DEP domain containing mTOR-interacting protein (DEPTOR) was originally identified as an in vivo dual inhibitor of mechanistic target of rapamycin (mTOR). It was recently reported to be involved in renal physiology and pathology in vitro; however, its detailed roles and mechanisms in vivo are completely unknown. We observed that DEPTOR expression in the kidney was markedly increased on day 3 after cisplatin treatment, at which time cell apoptosis peaked, implicating DEPTOR in cisplatin-induced acute kidney injury (AKI). We then used the Cre–LoxP system to generate mutant mice in which the DEPTOR gene was specifically deleted in the proximal tubule cells. DEPTOR deficiency did not alter the renal histology or functions in the saline-treated group, indicating that DEPTOR is not essential for kidney function under physiological conditions. Interestingly, DEPTOR deletion extensively preserved the renal histology and maintained the kidney functions after cisplatin treatment, suggesting that the absence of DEPTOR ameliorates cisplatin-induced AKI. Mechanistically, DEPTOR modulated p38 MAPK signaling and TNFα production in vivo and in vitro, rather than mTOR signaling, thus moderating the inflammatory response and cell apoptosis induced by cisplatin. Collectively, our findings demonstrate the roles and mechanisms of DEPTOR in the regulation of the renal physiology and pathology, and demonstrate that the loss of DEPTOR in the proximal tubules protects against cisplatin-induced AKI.
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影响因子：
16
作者：
Gao D;Inuzuka H;Tan MK;Fukushima H;Locasale JW;Liu P;Wan L;Zhai B;Chin YR;Shaik S;Lyssiotis CA;Gygi SP;Toker A;Cantley LC;Asara JM;Harper JW;Wei W
通讯作者：
Wei W
DOI：
10.1152/ajprenal.1996.270.4.f700
发表时间：
1996-04-01
期刊：
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL FLUID AND ELECTROLYTE PHYSIOLOGY
影响因子：
--
作者：
Lieberthal, W;Triaca, V;Levine, J
通讯作者：
Levine, J
影响因子：
64.5
作者：
Peterson TR;Laplante M;Thoreen CC;Sancak Y;Kang SA;Kuehl WM;Gray NS;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
15.9
作者：
Ramesh, G;Reeves, WB
通讯作者：
Reeves, WB
DOI：
10.1073/pnas.1402352111
发表时间：
2014-07-08
影响因子：
11.1
作者：
Grahammer, Florian;Haenisch, Nora;Huber, Tobias B.
通讯作者：
Huber, Tobias B.