Roles of mTOR complexes in the kidney: implications for renal disease and transplantation.
Roles of mTOR complexes in the kidney: implications for renal disease and transplantation.
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DOI：
10.1038/nrneph.2016.108
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Thomson AW
中科院分区：
文献类型：
--
作者：
Fantus D;Rogers NM;Grahammer F;Huber TB;Thomson AW
mTOR通路在细胞代谢、生长和增殖的调节中具有核心作用。涉及肾细胞群中mTOR复合物（mTORC 1和mTORC 2）的选择性基因靶向和/或药理学mTOR抑制的研究揭示了mTOR在足细胞稳态和肾小管转运中的重要作用。在了解mTOR在肾损伤、多囊肾病和肾小球疾病（包括糖尿病肾病）中的作用方面也取得了重要进展。对mTORC 1和mTORC 2在调节免疫细胞稳态和功能中的作用的新见解有助于提高对mTOR靶向对免疫应答的复杂影响的理解，包括影响新发肾脏疾病和肾移植结局的影响。在临床肾移植方面的丰富经验已导致患者在移植后不同时间从钙调磷酸酶抑制剂成功转换为mTOR抑制剂，具有良好的长期移植功能。然而，由于mTOR抑制剂相关毒性，这种做法的广泛使用受到限制。与其他方案相比，mTOR抑制剂的独特属性包括鳞状细胞癌和巨细胞病毒感染的发生率降低。随着对mTORC 1和mTORC 2驱动肾脏疾病发病机制的理解的进展，mTOR通路靶向的临床研究将能够测试不断发展的假设。
The mTOR pathway has a central role in the regulation of cell metabolism, growth and proliferation. Studies involving selective gene targeting of mTOR complexes (mTORC1 and mTORC2) in renal cell populations and/or pharmacologic mTOR inhibition have revealed important roles of mTOR in podocyte homeostasis and tubular transport. Important advances have also been made in understanding the role of mTOR in renal injury, polycystic kidney disease and glomerular diseases, including diabetic nephropathy. Novel insights into the roles of mTORC1 and mTORC2 in regulation of immune cell homeostasis and function are helping to improve understanding of the complex effects of mTOR targeting on immune responses, including those that impact both de novo renal disease and renal allograft outcomes. Extensive experience in clinical renal transplantation has resulted in successful conversion of patients from calcineurin inhibitors to mTOR inhibitors at various times post-transplantation, with excellent long-term graft function. Widespread use of this practice has, however, been limited owing to mTOR-inhibitor-related toxicities. Unique attributes of mTOR inhibitors include reduced rates of squamous cell carcinoma and cytomegalovirus infection compared to other regimens. As understanding of the mechanisms by which mTORC1 and mTORC2 drive the pathogenesis of renal disease progresses, clinical studies of mTOR pathway targeting will enable testing of evolving hypotheses.
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