RhoA/rho kinase signaling reduces connexin43 expression in high glucose-treated glomerular mesangial cells with zonula occludens-1 involvement.
RhoA/rho kinase signaling reduces connexin43 expression in high glucose-treated glomerular mesangial cells with zonula occludens-1 involvement.
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DOI：
10.1016/j.yexcr.2014.07.019
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发表时间：
2014-10
影响因子：
3.7
通讯作者：
Xi Xie;Cheng Chen;Kaipeng Huang;Shaogui Wang;Jie Hao;Junying Huang;Heqing Huang
中科院分区：
文献类型：
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作者：
Xi Xie;Cheng Chen;Kaipeng Huang;Shaogui Wang;Jie Hao;Junying Huang;Heqing Huang
RhoA/Rho激酶（ROCK）信号通路参与糖尿病肾病（DN）的发病机制。在糖尿病动物的肾脏中发现了连接蛋白43（Cx43）的表达改变。这两种蛋白质均能调节高糖处理的肾小球系膜细胞（GMCs）核因子-κ B（NF-κB）活化。本研究旨在探讨RhoA/ROCK信号通路与Cx43在DN发病机制中的关系。我们发现，上调Cx43表达可抑制RhoA/ROCK信号诱导的GMCs NF-κB p65核转位。RhoA/ROCK信号的抑制减弱了高糖诱导的Cx43的降低。在高糖处理的GMCs中观察到F-肌动蛋白积累和紧密小带-1（ZO-1）与Cx43之间增强的相互作用。ZO-1耗竭或F-肌动蛋白形成的破坏也抑制了高糖诱导的Cx43蛋白水平的降低。总之，激活的RhoA/ROCK信号转导诱导高糖培养的GMCs中Cx43降解，这取决于F-actin的调节。RhoA/ROCK信号诱导的F-actin增加促进ZO-1和Cx43之间的结合，这可能触发了高糖处理的GMCs中NF-κB激活的Cx43内吞作用。
RhoA/Rho kinase (ROCK) signaling has been suggested to be involved in diabetic nephropathy (DN) pathogenesis. Altered expression of connexin43 (Cx43) has been found in kidneys of diabetic animals. Both of them have been found to regulate nuclear factor kappa-B (NF-κB) activation in high glucose-treated glomerular mesangial cells (GMCs). The aim of this study was to investigate the relationship between RhoA/ROCK signaling and Cx43 in the DN pathogenesis. We found that upregulation of Cx43 expression inhibited NF-κB p65 nuclear translocation induced by RhoA/ROCK signaling in GMCs. Inhibition of RhoA/ROCK signaling attenuated the high glucose-induced decrease in Cx43. F-actin accumulation and an enhanced interaction between zonula occludens-1 (ZO-1) and Cx43 were observed in high glucose-treated GMCs. ZO-1 depletion or disruption of F-actin formation also inhibited the reduction in Cx43 protein levels induced by high glucose. In conclusion, activated RhoA/ROCK signaling induces Cx43 degradation in GMCs cultured in high glucose, depending on F-actin regulation. Increased F-actin induced by RhoA/ROCK signaling promotes the association between ZO-1 and Cx43, which possibly triggered Cx43 endocytosis, a mechanism of NF-κB activation in high glucose-treated GMCs.