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ZEB1 通过 SP1 和 SP3 介导角膜内皮间充质转化中的纤维化。

ZEB1 Mediates Fibrosis in Corneal Endothelial Mesenchymal Transition Through SP1 and SP3.

机构信息

,.

出版信息

Invest Ophthalmol Vis Sci. 2020 Jul 1;61(8):41. doi: 10.1167/iovs.61.8.41.

DOI:10.1167/iovs.61.8.41
PMID:32721022
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7425726/
Abstract

PURPOSE

ZEB1 is induced during endothelial-mesenchymal transition (EnMT) in the cornea. Induction of SP1 and SP3 by ZEB1 along with identification of putative SP1 and SP3 binding sites in promoters of EnMT-associated gene lead us to investigate their roles in retrocorneal membrane formation in the corneal endothelium.

METHODS

Expressions of SP1, SP3, and EnMT associated genes were analyzed by immunoblotting and semiquantitative reverse transcription polymerase chain reaction. Accell SMARTpool siRNAs targeting ZEB1, SP1, and SP3 were used for gene knockdown. SP1 and SP3 binding to promoters of EnMT associated genes was investigated by chromatin immunoprecipitation assay. Corneal endothelium in mice was surgically injured in vivo under direct visualization.

RESULTS

Transient Fibroblast Growth Factor 2 stimulation increased the expression of both SP1 and SP3 in the human corneal endothelium ex vivo. ZEB1 siRNA knockdown inhibited FGF2-induced SP1 mRNA and protein but not the expression of SP3. FGF2-induced expression of EnMT-related genes, such as fibronectin, vimentin, and type I collagen, was reduced by both SP1 and SP3 siRNA knockdown, with inhibition of SP1 having a greater inhibitory effect than SP3. Additionally, although SP1 and SP3 proteins were found to bind together, SP1 and SP3 could bind to the same promoter binding sites of EnMT-related genes in the absence of the other. Moreover, siRNA knockdown of Zeb1 inhibited injury-dependent RCM formation in mouse corneal endothelium in vivo.

CONCLUSIONS

Zeb1, through SP1 and SP3, plays a central role in mesenchymal transition induced fibrosis in the corneal endothelium and suggests that Zeb1 could be targeted to inhibit anterior segment fibrosis.

摘要

目的

ZEB1 在角膜的内皮-间质转化（EnMT）过程中被诱导。ZEB1 诱导 SP1 和 SP3 的表达，并鉴定 EnMT 相关基因启动子中潜在的 SP1 和 SP3 结合位点，这促使我们研究它们在角膜内皮后弹力膜形成中的作用。

方法

通过免疫印迹和半定量逆转录聚合酶链反应分析 SP1、SP3 和 EnMT 相关基因的表达。使用针对 ZEB1、SP1 和 SP3 的 Accell SMARTpool siRNA 进行基因敲低。通过染色质免疫沉淀分析研究 SP1 和 SP3 与 EnMT 相关基因启动子的结合。在体内直视下对小鼠角膜内皮进行手术损伤。

结果

瞬时碱性成纤维细胞生长因子 2（FGF2）刺激可增加体外人角膜内皮中 SP1 和 SP3 的表达。ZEB1 siRNA 敲低抑制了 FGF2 诱导的 SP1 mRNA 和蛋白表达，但不影响 SP3 的表达。FGF2 诱导的纤维连接蛋白、波形蛋白和 I 型胶原等 EnMT 相关基因的表达，通过 SP1 和 SP3 siRNA 敲低均降低，SP1 抑制作用大于 SP3。此外，尽管发现 SP1 和 SP3 蛋白结合在一起，但 SP1 和 SP3 可以在没有另一种蛋白的情况下结合到 EnMT 相关基因的相同启动子结合位点。此外，Zeb1 siRNA 敲低抑制了体内小鼠角膜内皮损伤依赖性后弹力膜形成。

结论

Zeb1 通过 SP1 和 SP3 在角膜内皮间质转化诱导的纤维化中发挥核心作用，并表明 Zeb1 可作为靶点抑制前节纤维化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/2ee39f2ee68d/iovs-61-8-41-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/4bcf6337f7c6/iovs-61-8-41-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/99b0f1cf610f/iovs-61-8-41-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/7c4c7adc685a/iovs-61-8-41-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/766e08f0777d/iovs-61-8-41-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/cf62b8a12299/iovs-61-8-41-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/e8c399047606/iovs-61-8-41-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/26cade54d7c6/iovs-61-8-41-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/fcacadafe742/iovs-61-8-41-f008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/2ee39f2ee68d/iovs-61-8-41-f009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/4bcf6337f7c6/iovs-61-8-41-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/99b0f1cf610f/iovs-61-8-41-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/7c4c7adc685a/iovs-61-8-41-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/766e08f0777d/iovs-61-8-41-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/cf62b8a12299/iovs-61-8-41-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/e8c399047606/iovs-61-8-41-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/26cade54d7c6/iovs-61-8-41-f007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/fcacadafe742/iovs-61-8-41-f008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0a08/7425726/2ee39f2ee68d/iovs-61-8-41-f009.jpg

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