缝隙连接蛋白 43 介导高糖诱导的肾小球系膜细胞中 NF-κB 信号通路的激活：c-Src 的参与。

Connexin43 mediates NF-κB signalling activation induced by high glucose in GMCs: involvement of c-Src.

机构信息

Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

出版信息

Cell Commun Signal. 2013 May 29;11(1):38. doi: 10.1186/1478-811X-11-38.

BACKGROUND

Nuclear factor kappa-B (NF-κB) signalling plays an important role in diabetic nephropathy. Altered expression of connexin43 (Cx43) has been found in kidneys of diabetic animals. The aim of the current study was to investigate the role of Cx43 in the activation of NF-κB induced by high glucose in glomerular mesangial cells (GMCs) and to determine whether c-Src is involved in this process.

RESULTS

We found that downregulation of Cx43 expression induced by high glucose activated NF-κB in GMCs. Orverexpression of Cx43 attenuated NF-κB p65 nuclear translocation induced by high glucose. High glucose inhibited the interaction between Cx43 and c-Src, and enhanced the interaction between c-Src and IκB-α. PP2, a c-Src inhibitor, also inhibited the tyrosine phosphorylation of IκB-α and NF-κB p65 nuclear translocation induced by high glucose. Furthermore, overexpression of Cx43 or inhibition of c-Src attenuated the upregulation of intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-beta 1 (TGF-β1) and fibronectin (FN) expression induced by high glucose.

CONCLUSIONS

In conclusion, downregulation of Cx43 in GMCs induced by high glucose activates c-Src, which in turn promotes interaction between c-Src and IκB-α and contributes to NF-κB activation in GMCs, leading to renal inflammation.

背景

核因子 kappa-B（NF-κB）信号通路在糖尿病肾病中发挥着重要作用。已发现糖尿病动物肾脏中连接蛋白 43（Cx43）的表达发生改变。本研究旨在探讨 Cx43 在高糖诱导的肾小球系膜细胞（GMC）中 NF-κB 激活中的作用，并确定 c-Src 是否参与这一过程。

结果

我们发现高糖诱导的 Cx43 表达下调可激活 GMC 中的 NF-κB。高糖过表达 Cx43 可减弱 NF-κB p65 核转位。高糖抑制 Cx43 与 c-Src 之间的相互作用，增强 c-Src 与 IκB-α之间的相互作用。c-Src 抑制剂 PP2 也可抑制高糖诱导的 IκB-α酪氨酸磷酸化和 NF-κB p65 核转位。此外，Cx43 的过表达或 c-Src 的抑制可减弱高糖诱导的细胞间黏附分子-1（ICAM-1）、转化生长因子-β1（TGF-β1）和纤维连接蛋白（FN）表达的上调。