High glucose-induced apoptosis in cultured podocytes involves TRPC6-dependent calcium entry via the RhoA/ROCK pathway.
High glucose-induced apoptosis in cultured podocytes involves TRPC6-dependent calcium entry via the RhoA/ROCK pathway.
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高葡萄糖诱导的培养足细胞凋亡涉及 TRPC6 依赖性钙通过 RhoA/ROCK 途径进入。
DOI：
10.1016/j.bbrc.2013.03.087
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
焦军东
中科院分区：
文献类型：
--
作者：
焦军东
越来越多的证据表明足细胞凋亡是糖尿病肾病发展的关键事件。然而，这种细胞凋亡的潜在机制仍然知之甚少。在这项研究中，我们报道了高水平的葡萄糖增强了TRPC6和TRPC6依赖性Ca2+内流的表达，但葡萄糖水平不影响TRPC1和TRPC5的表达。通过siRNA干扰敲低TRPC6可减弱葡萄糖诱导的足细胞凋亡的增加。高葡萄糖水平也会增加ROS的产生；n -乙酰-l-半胱氨酸对ROS活性的抑制减弱了高糖诱导的TRPC6表达和Ca2+内流的增加。外源性h2o2处理模拟了高糖反应，导致TRPC6表达和Ca2+内流增加。综上所述，这些数据表明高葡萄糖水平诱导ROS，从而介导TRPC6表达和Ca2+内流。由于TRPC6激活后RhoA活性增加，我们研究了TRPC6是否通过RhoA/ROCK途径参与高糖诱导的细胞凋亡。我们报道，高葡萄糖水平导致RhoA活性增加，而这种影响被TRPC6的敲除所消除。此外，ROCK抑制剂Y27632对RhoA/ROCK通路的抑制也能减轻高糖诱导的细胞凋亡。我们得出结论，TRPC6通过RhoA/ROCK途径参与高糖诱导的足细胞凋亡。
Increasing evidence indicates that podocyte apoptosis is a key event in the development of diabetic nephrology. However, the underlying mechanism of this apoptosis remains poorly understood. In this study, we report that high levels of glucose enhanced the expression of TRPC6 and TRPC6-dependent Ca2+influx, but glucose levels did not affect TRPC1 and TRPC5 expression. TRPC6 knockdown by siRNA interference attenuated the observed increase in glucose-induced podocyte apoptosis. High glucose levels also increased the generation of ROS; inhibition of ROS activity by N-acetyl-l-cysteine attenuated the high glucose-induced increase in TRPC6 expression and Ca2+influx. Exogenous treatment with H2O2mimicked the high glucose response, resulting in an increase in TRPC6 expression and Ca2+influx. Taken together, these data suggest that high glucose levels induce ROS, thereby mediating TRPC6 expression and Ca2+influx. Because RhoA activity is increased following TRPC6 activation, we investigated whether TRPC6 is involved in high glucose-induced apoptosis via the RhoA/ROCK pathway. We report that high glucose levels produced an increase in RhoA activity, and this effect was abolished by the knockdown of TRPC6. Moreover, inhibition of the RhoA/ROCK pathway by a ROCK inhibitor, Y27632, also attenuated high glucose-induced apoptosis. We conclude that TRPC6 is involved in high glucose-induced podocyte apoptosis through the RhoA/ROCK pathway.
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