Connexin43 regulates high glucose-induced expression of fibronectin, ICAM-1 and TGF-β1 via Nrf2/ARE pathway in glomerular mesangial cells
Connexin43 regulates high glucose-induced expression of fibronectin, ICAM-1 and TGF-β1 via Nrf2/ARE pathway in glomerular mesangial cells
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Connexin43 通过 Nrf2/ARE 通路调节高糖诱导的肾小球系膜细胞中纤连蛋白、ICAM-1 和 TGF-β1 的表达
DOI：
10.1016/j.freeradbiomed.2016.11.015
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发表时间：
2017-01-01
影响因子：
7.4
通讯作者：
Huang, Heqing
中科院分区：
文献类型：
--
作者：
Chen, Zhiquan;Xie, Xi;Huang, Heqing
Nrf 2/ARE信号通路是科普氧化应激的重要细胞防御系统，在糖尿病状态下，Nrf 2/ARE信号通路被适应性地激活，而糖尿病状态下Nrf 2/ARE信号通路不能有效抵抗高血糖引起的氧化应激。我们先前已经证明连接蛋白43（Cx43）通过c-Src减弱肾纤维化。然而，其基本机制需要进一步澄清。研究表明Cx43具有抗氧化能力。本研究旨在探讨Cx43是否通过激活Nrf 2/ARE通路对糖尿病肾纤维化具有保护作用，并探讨其分子机制。结果表明：（1）糖尿病大鼠肾脏Cx43表达降低，c-Src活性升高，高糖处理的GMCs过度表达Cx43抑制FN、ICAM-1和TGF-β 1的蛋白表达，高糖处理的GMCs对Nrf 2/ARE信号通路产生适应性反应，高糖处理的GMCs过度表达Cx43抑制FN、ICAM-1和TGF-β 1的表达。（4）Cx43通过增强Nrf 2/ARE信号通路减少高糖条件下ROS的产生：（5）抑制c-Src活性促进Nrf 2在细胞核内的积累;（6）高糖培养的GMCs中Cx43过表达抑制c-Src活性及c-Src与Nrf 2的相互作用。提示Cx43可能通过抑制c-Src的活性，抑制Nrf 2的核输出，增强Nrf 2/ARE通路的激活，进而降低FN、ICAM-1、TGF-β 1的表达，减轻糖尿病肾纤维化。
Nrf2/ARE signaling pathway is a crucial cellular defense system to cope with oxidative stress, which is adaptively activated, in diabetic condition that is not efficient enough to resist the oxidative stress provoked by hyperglycemia. We have previously demonstrated that Connexin43 (Cx43) attenuates renal fibrosis through c-Src. However, the underlying mechanisms need to be further clarified. It has been reported that Cx43 possesses the ability of anti-oxidative. The current study aimed to determine if Cx43 exerts protective effects on renal fibrosis in diabetes via activation of Nrf2/ARE pathway and explore the underlying molecular mechanisms. The following findings were observed: (1) Cx43 expression decreased and c-Src activity increased in kidneys of diabetic animals; (2) Over-expressed Cx43 in high glucose treated GMCs inhibited protein levels of FN, ICAM-1 and TGF-beta 1; (3) Nrf2/ARE signaling adaptively responded to high glucose treatment in GMCs; (4) Cx43 reduced ROS generation by boost Nrf2/ARE signaling under high glucose condition; (5) Inhibition of c-Src activity promoted nucleus accumulation of Nrf2; (6) Over-expressed Cx43 inhibited c-Src activity and the interaction between c-Src and Nrf2 in GMCs cultured in high glucose. Thus we propose that Cx43 might enhance the activation of Nrf2/ARE pathway by means of inhibiting c-Src activity to hinder the nuclear export of Nrf2, and then reduce expression of FN, ICAM-1, TGF-beta 1, ultimately attenuating renal fibrosis in diabetes.