Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
Renal Division, University Hospital Tübingen, 72076 Tübingen, Germany;
Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):E2817-26. doi: 10.1073/pnas.1402352111. Epub 2014 Jun 23.
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.
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剂。尽管 mTORC1 抑制剂在临床上广泛应用，但 mTORC1 在肾小管功能和肾脏内稳态中的作用仍不清楚。通过在肾小管上皮细胞中使用组成型和诱导型条件性 Raptor 等位基因缺失，我们发现 mTORC1 缺乏会导致明显的浓缩缺陷、管状细胞丢失和缓慢进展的肾纤维化。转录谱分析显示，mTORC1 通过控制线粒体代谢和生物发生以及涉及逆流倍增和尿液浓缩的细胞间转运过程来维持肾小管内稳态。尽管 mTORC2 部分补偿了 mTORC1 的缺失，但暴露于缺血再灌注损伤会加重 mTORC1 缺陷小鼠的肾小管损伤，并导致明显的细胞凋亡、增殖率降低和恢复延迟。这些发现确定 mTORC1 是肾小管能量代谢的重要调节剂，也是缺血应激反应的关键组成部分。
