mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress
mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress
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DOI：
10.1073/pnas.1402352111
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发表时间：
2014-07-08
影响因子：
11.1
通讯作者：
Huber, Tobias B.
中科院分区：
文献类型：
--
作者：
Grahammer, Florian;Haenisch, Nora;Huber, Tobias B.
哺乳动物雷帕霉素靶蛋白复合物1 （mTORC1）是细胞代谢和自噬的关键调节因子。尽管临床上广泛使用mTORC1抑制剂，但mTORC1在肾小管功能和肾脏稳态中的作用仍然难以捉摸。通过对肾小管上皮细胞中条件型Raptor等位基因的组成性和诱导性缺失，我们发现mTORC1缺失导致了明显的集中缺陷、小管细胞的丢失和缓慢进行性肾纤维化。转录谱分析显示，mTORC1通过控制线粒体代谢和生物发生以及参与逆流增殖和尿浓度的跨细胞运输过程来维持肾小管稳态。尽管mTORC2部分补偿了mTORC1的缺失，但缺血和再灌注损伤加重了mTORC1缺失小鼠的小管损伤，并导致明显的细胞凋亡、增殖率降低和恢复延迟。这些发现表明mTORC1是小管能量代谢的重要调节因子，也是缺血应激反应的重要组成部分。
Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTORC1 inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By using constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells, and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in countercurrent multiplication and urine concentration. Although mTORC2 partially compensated for the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice and caused pronounced apoptosis, diminished proliferation rates, and delayed recovery. These findings identify mTORC1 as an important regulator of tubular energy metabolism and as a crucial component of ischemic stress responses.