Blockade of mTORC1‐NOX signaling pathway inhibits TGF‐β1‐mediated senescence‐like structural alterations of the retinal pigment epithelium

mTORC1型 视网膜色素上皮 细胞生物学 封锁 信号转导 衰老 视网膜 上皮 转化生长因子 化学 PI3K/AKT/mTOR通路 生物 受体 生物化学 遗传学
作者
Seok Jae Lee,Soo‐Jin Kim,Dong Hyun Jo,Kyu‐Sang Park,Jeong Hun Kim
出处
期刊:The FASEB Journal [Wiley]
卷期号:35 (3) 被引量:7
标识
DOI:10.1096/fj.202001939rr
摘要

The retinal pigment epithelium (RPE) undergoes characteristic structural changes and epithelial-mesenchymal transition (EMT) during normal aging, which are exacerbated in age-related macular degeneration (AMD). Although the pathogenic mechanisms of aging and AMD remain unclear, transforming growth factor-β1 (TGF-β1) is known to induce oxidative stress, morphometric changes, and EMT as a senescence-promoting factor. In this study, we examined whether intravitreal injection of TGF-β1 into the mouse eye elicits senescence-like morphological alterations in the RPE and if this can be prevented by suppressing mammalian target of rapamycin complex 1 (mTORC1) or NADPH oxidase (NOX) signaling. We verified that intravitreal TGF-β1-induced stress fiber formation and EMT in RPE cells, along with age-associated morphometric changes, including increased variation in cell size and reduced cell density. In RPE cells, exogenous TGF-β1 increased endogenous expression of TGF-β1 and upregulated Smad3-ERK1/2-mTORC1 signaling, increasing reactive oxygen species (ROS) production and EMT. We demonstrated that inhibition of the mTORC1-NOX4 pathway by pretreatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-dependent protein kinase, or GKT137831, a NOX1/4 inhibitor, decreased ROS generation, prevented stress fiber formation, attenuated EMT, and improved the regularity of the RPE structure in vitro and in vivo. These results suggest that intravitreal TGF-β1 injection could be used as a screening model to investigate the aging-related structural and functional changes to the RPE. Furthermore, the regulation of TGF-β-mTORC1-NOX signaling could be a potential therapeutic target for reducing pathogenic alterations in aged RPE and AMD.
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