mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes
mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes
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DOI：
10.1152/ajprenal.90319.2008
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发表时间：
2009-02-01
影响因子：
4.2
通讯作者：
Weide, Thomas
中科院分区：
文献类型：
--
作者：
Vollenbroeker, Beate;George, Britta;Weide, Thomas
Vollenbroker B、George B、Wolfgart M、Saleem MA、Pavenstadt H、Weide T。mTOR 调节足细胞中裂隙隔膜蛋白和细胞骨架结构的表达。 Am J Physiol Renal Physiol 296：F418-F426，2009。首次发表于 2008 年 11 月 19 日； doi:10.1152/ajprenal.90319.2008.-雷帕霉素 (mTOR) 抑制剂的免疫抑制哺乳动物靶标可引起蛋白尿，特别是在肾移植和心脏移植患者中。足细胞在建立血尿过滤屏障的选择性通透性方面发挥着重要作用。这些细胞的损伤会导致蛋白尿，这是大多数肾小球疾病的标志。有趣的是，一些移植患者在接受 mTOR 抑制剂治疗后可能会出现足细胞损伤和局灶性节段性肾小球硬化。为了研究 mTOR 抑制剂诱导足细胞损伤的机制，我们分析了雷帕霉素对人足细胞 mTOR 信号传导和细胞功能的影响。我们发现，延长雷帕霉素治疗会降低总 mTOR 的表达，这与 mTOR Ser(2448) 和 Ser(2481) 磷酸化水平降低相关。此外，雷帕霉素治疗可减少 rictor 表达和 mTORC2 形成，导致蛋白激酶 B Ser(473) 磷酸化减少。狭缝隔膜蛋白去氧肾上腺素和瞬时受体电位阳离子通道6以及细胞骨架衔接蛋白Nck的表达水平显着降低。此外，雷帕霉素降低了细胞粘附和细胞运动，同时增强了富含肌动蛋白的点状结构的形成。我们的数据提供了新的分子见解，解释了雷帕霉素治疗导致的 mTOR 功能不平衡会影响足细胞中的哪些途径和分子。
Vollenbroker B, George B, Wolfgart M, Saleem MA, Pavenstadt H, Weide T. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes. Am J Physiol Renal Physiol 296: F418-F426, 2009. First published November 19, 2008; doi:10.1152/ajprenal.90319.2008.-The immunosuppressive mammalian target of rapamycin ( mTOR) inhibitors can cause proteinuria, especially in kidney and heart transplanted patients. Podocytes play a major role in establishing the selective permeability of the blood-urine filtration barrier. Damage of these cells leads to proteinuria, a hallmark of most glomerular diseases. Interestingly, podocyte damage and focal segmental glomerulosclerosis can occur after treatment with an mTOR inhibitor in some transplant patients. To investigate the mechanisms of mTOR inhibitor-induced podocyte damage, we analyzed the effect of rapamycin on mTOR signaling and cellular function in human podocytes. We found that prolonged rapamycin treatment reduced the expression of total mTOR, which correlates with diminished levels of mTOR phosphorylation at Ser(2448) and Ser(2481). In addition, treatment with rapamycin reduced rictor expression and mTORC2 formation, resulting in a reduced phosphorylation of protein kinase B at Ser(473). The expression level of the slit-diaphragm proteins nephrin and transient receptor potential cation channel 6 as well as the cytoskeletal adaptor protein Nck significantly decreased. Moreover, rapamycin reduced cell adhesion and cell motility, which was accompanied by an enhanced formation of dot-like actin-rich structures. Our data provide new molecular insights explaining which pathways and molecules are affected in podocytes by an imbalanced mTOR function because of rapamycin treatment.