Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells
Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells
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洛伐他汀减弱环孢素 A 对培养的皮质集合管主细胞紧密连接和细胞凋亡的影响
DOI：
10.1152/ajprenal.00074.2013
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发表时间：
2013-08-01
影响因子：
4.2
通讯作者：
Ma, He-Ping
中科院分区：
文献类型：
--
作者：
Liu, Bing-Chen;Song, Xiang;Ma, He-Ping
我们使用小鼠皮质集合管主细胞（mpkCCD（c14）细胞系）作为模型，以确定他汀类药物是否减少环孢素A（CsA）对远端肾单位的有害影响。数据显示，用CsA处理细胞增加跨上皮阻力，并且CsA的作用被洛伐他汀废除。扫描离子电导显微镜显示CsA显著增加了紧密连接附近的细胞突起高度。相比之下，洛伐他汀消除了突起，甚至在细胞之间引起了适度的凹陷。蛋白质印迹分析和共聚焦显微镜显示，洛伐他汀也废除了CsA诱导的高度的紧密连接中的闭锁小带-1和胆固醇。相比之下，高浓度的CsA诱导细胞凋亡，这也被Lovastatin减弱，通过激活NADPH氧化酶增加细胞内活性氧，并增加p47（phox）的表达。持续处理细胞与洛伐他汀也诱导显着的细胞凋亡，这是衰减的CsA，但不升高细胞内的ROS。这些结果表明，CsA和洛伐他汀是有害的远端小管的主细胞，但通过ROS依赖性和ROS独立的凋亡途径，分别，他们抵消可能通过动员细胞胆固醇水平。
We used mouse cortical collecting duct principal cells (mpkCCD(c14) cell line) as a model to determine whether statins reduce the harmful effects of cyclosporine A (CsA) on the distal nephron. The data showed that treatment of cells with CsA increased transepithelial resistance and that the effect of CsA was abolished by lovastatin. Scanning ion conductance microscopy showed that CsA significantly increased the height of cellular protrusions near tight junctions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between cells. Western blot analysis and confocal microscopy showed that lovastatin also abolished CsA-induced elevation of both zonula occludens-1 and cholesterol in tight junctions. In contrast, a high concentration of CsA induced apoptosis, which was also attenuated by lovastatin, elevated intracellular ROS via activation of NADPH oxidase, and increased the expression of p47(phox). Sustained treatment of cells with lovastatin also induced significant apoptosis, which was attenuated by CsA, but did not elevate intracellular ROS. These results indicate that both CsA and lovastatin are harmful to principal cells of the distal tubule, but via ROS-dependent and ROS-independent apoptotic pathways, respectively, and that they counteract probably via mobilization of cellular cholesterol levels.