Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes
Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes
复制标题
牛磺酸熊去氧胆酸对培养小鼠足细胞内质网应激和晚期糖基化终产物诱导的细胞凋亡的影响
DOI：
10.1159/000148209
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发表时间：
2008-01-01
影响因子：
4.2
通讯作者：
Liu, Chao
中科院分区：
文献类型：
--
作者：
Chen, Yu;Liu, Cui Ping;Liu, Chao
背景：死亡受体的激活和线粒体损伤是众所周知的常见细胞凋亡途径。最近，报道了一种通过内质网（ER）应激的新途径。方法：我们评估了牛磺熊去氧胆酸 (TUDCA) 在抑制 ER 应激中的作用及其对晚期糖基化终末产物 (AGE) 诱导的小鼠足细胞凋亡的保护作用。将足细胞与逐渐增加剂量的 AGE 一起孵育不同的时间段。通过流式细胞术同时检测碘化丙啶表达和膜联蛋白V结合来定量测定细胞凋亡。通过蛋白质印迹法测定葡萄糖调节蛋白 78（ER 应激标记物）的表达水平。通过激光共聚焦显微镜和 Ca2+ 指示剂 Fluo-3 标记记录细胞内钙浓度 ([Ca2+](i))。结果：与牛血清白蛋白相比，AGEs 诱导足细胞凋亡，并以剂量和时间依赖性方式增加葡萄糖调节蛋白 78 的表达。这些变化伴随着足细胞 [Ca2+](i) 的快速升高。 TUDCA 能够消除 AGEs 诱导的葡萄糖调节蛋白 78 的表达，并随后以剂量依赖性方式抑制细胞凋亡。结论：我们认为 ER 应激在 AGE 诱导的细胞凋亡中发挥重要作用，TUDCA 通过阻断 ER 应激介导的细胞凋亡途径来预防细胞凋亡。 TUDCA 作用的这种新机制为 AGE 诱导的糖尿病肾病小鼠足细胞凋亡提供了新的干预方法。版权所有 (C) 2008 S. Karger AG，巴塞尔。
Background: Activations of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. Methods: We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of ER stress and its protective effect on advanced glycation end products (AGEs)-induced apoptosis in murine podocytes. Podocytes were incubated with increasing doses of AGEs for variable time periods. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously. Level of glucose-regulated protein 78 (ER stress marker) expression was determined by Western blot. Intracellular calcium concentration ([Ca2+](i)) was recorded by a laser confocal microscope and the Ca2+ indicator Fluo-3 labeling. Results: AGEs induced podocyte apoptosis and increased the expression of glucose-regulated protein 78 in a dose-and time-dependent manner as compared with bovine serum albumin. These changes were accompanied by a rapid rise in [Ca2+](i) of podocytes. TUDCA was capable of abolishing AGEs-induced expression of glucose-regulated protein 78 and subsequently inhibited apoptosis in a dose-dependent manner. Conclusion: We propose that ER stress plays an important role in AGEs-induced apoptosis and that TUDCA prevents apoptosis by blocking an ER stress-mediated apoptotic pathway. This novel mechanism of TUDCA action suggests new intervention methods for AGEs-induced apoptosis of mouse podocytes in diabetic nephropathy. Copyright (C) 2008 S. Karger AG, Basel.