The reactive oxygen species (ROS) producing enzyme, NADPH oxidase 4 (Nox4), is upregulated in response to TGFβ in lens epithelial cells in vitro, and its selective inhibition was shown to block aspects of TGFβ-induced epithelial-mesenchymal transition (EMT). In the present in situ study we validate the role(s) of Nox4 in TGFβ-induced lens EMT leading to anterior subcapsular cataract (ASC) formation. Mice overexpressing TGFβ in the lens, that develop ASC, were crossed to Nox4-deficient mice. When comparing mice overexpressing TGFβ in lens, to mice that were also deficient for Nox4, we see the delayed onset of cataract, along with a delay in EMT protein markers normally associated with TGFβ-induced fibrotic cataracts. In the absence of Nox4, we also see elevated levels of ERK1/2 activity that was shown to be required for TGFβ/Smad2/3-signaling. qRT-PCR revealed upregulation of Nox2 and its regulatory subunit in TGFβ-overexpressing lens epithelial cells devoid of Nox4. Taken together, these findings provide an improved platform to delineate putative Nox4 (and ROS) interactions with Smad2/3 and/or ERK1/2, in particular in the development of fibrotic diseases, such as specific forms of cataract.

译文

活性氧 (ROS) 产生酶NADPH氧化酶4 (Nox4) 在体外晶状体上皮细胞中响应tgf β 而上调,其选择性抑制被证明可阻断tgf β 诱导的上皮间质转化 (EMT)。在目前的原位研究中,我们验证了Nox4在tgf β 诱导的晶状体EMT中导致前囊下白内障 (ASC) 形成的作用。将在晶状体中过表达tgf β 的小鼠杂交至Nox4-deficient小鼠,以形成ASC。当将晶状体中过表达tgf β 的小鼠与也缺乏Nox4的小鼠进行比较时,我们看到白内障的延迟发作,以及通常与tgf β 诱导的纤维化性白内障相关的EMT蛋白标记的延迟。在没有Nox4的情况下,我们还看到ERK1/2活性水平升高,这被证明是tgf β/Smad2/3信号传导所必需的。qRT-PCR揭示了在没有nox4的tgf β 过表达的晶状体上皮细胞中Nox2及其调节亚基的上调。总之,这些发现提供了一个改进的平台来描述假定的Nox4 (和ROS) 与Smad2/3和/或ERK1/2的相互作用,特别是在纤维化疾病 (例如特定形式的白内障) 的发展中。

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