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Connexin43 Hemichannels Contribute to Cadmium-Induced Oxidative Stress and Cell Injury

By Xin Fang, Tao Huang, Ying Zhu, Qiaojing Yan, Yuan Chi, Jean X. Jiang, Peiyu Wang, Hiroyuki Matsue, Masanori Kitamura and Jian Yao


We investigated the potential involvement of connexin hemichannels in cadmium ions (Cd2+)-elicited cell injury. Transfection of LLC-PK1 cells with a wild-type connexin43 (Cx43) sensitized them to Cd2+-elicited cell injury. The cell susceptibility to Cd2+ was increased by depletion of glutathione (GSH) with DL-buthionine-[S,R]-sulfoximine, and decreased by N-acetyl-cysteine or glutathione reduced ethyl ester. Fibroblasts derived from Cx43 wild-type (Cx43+/+) and knockout (Cx43-/-) fetal littermates displayed different susceptibility to Cd2+. Cd2+ induced a higher concentration of reactive oxygen species, a stronger activation c-Jun N-terminal kinase, and significantly more severe cell injury in Cx43+/+ fibroblasts, as compared with Cx43-/- fibroblasts. Cd2+ caused a reduction in intracellular GSH, whereas it elevated extracellular GSH. This effect of Cd2+ was more dramatic in Cx43+/+ than Cx43-/- fibroblasts. Treatment of Cx43+/+ fibroblasts with Cd2+ caused a Cx43 hemichannel-dependent influx of Lucifer Yellow and efflux of ATP. Collectively, our study demonstrates that Cx43 sensitizes cells to Cd2+-initiated cytotoxicity, possibly through hemichannel-mediated effects on intracellular oxidative status. Antioxid. Redox Signal. 14, 2427–2439

Topics: Original Research Communications
Publisher: Mary Ann Liebert, Inc.
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Provided by: PubMed Central
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