Open AccessAQP1 suppression by ATF4 triggers trabecular meshwork tissue remodelling in ET‐1‐induced POAG
Author(s) -
Zhao Yingying,
Zhu Huazhang,
Yang Yangfan,
Ye Yiming,
Yao Youli,
Huang Xiaoyan,
Zhang Yixiang,
Shu Xingsheng,
Chen Xianxiong,
Yang Yatao,
Ma Junxian,
Cheng Le,
Wang Xiaomei,
Ying Ying
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15032
Subject(s) - trabecular meshwork , atf4 , extracellular matrix , microbiology and biotechnology , glaucoma , transcription factor , in vivo , chemistry , aquaporin 1 , biology , cancer research , unfolded protein response , neuroscience , genetics , gene , endoplasmic reticulum , mechanical engineering , water channel , engineering , inlet
Primary open‐angle glaucoma (POAG) is the second leading cause of irreversible blindness worldwide. Increased endothelin‐1 (ET‐1) has been observed in aqueous humour (AH) of POAG patients, resulting in an increase in the out‐flow resistance of the AH. However, the underlining mechanisms remain elusive. Using established in vivo and in vitro POAG models, we demonstrated that water channel Aquaporin 1 (AQP1) is down‐regulated in trabecular meshwork (TM) cells upon ET‐1 exposure, which causes a series of glaucomatous changes, including actin fibre reorganization, collagen production, extracellular matrix deposition and contractility alteration of TM cells. Ectopic expression of AQP1 can reverse ET‐1‐induced TM tissue remodelling, which requires the presence of β‐catenin. More importantly, we found that ET‐1‐induced AQP1 suppression is mediated by ATF4, a transcription factor of the unfolded protein response, which binds to the promoter of AQP1 and negatively regulates AQP1 transcription. Thus, we discovered a novel function of ATF4 in controlling the process of TM remodelling in ET‐1‐induced POAG through transcription suppression of AQP1. Our findings also detail a novel pathological mechanism and a potential therapeutic target for POAG.