Xiang, Yan, Fu, Ting, Xu, Qiongfang, Chen, Wei, Chen, Zhiqi, Guo, Jinming, Deng, Chaohua, Manyande, Anne ORCID: https://orcid.org/0000-0002-8257-0722, Wang, Ping, Zhang, Hong, Tian, Xuebi and Wang, Junming (2023) The effect of ET1-CTGF mediated pathway on the accumulation of extracellular matrix in the trabecular meshwork and its contribution to the increase in IOP. International Ophthalmology, 43 (11). pp. 3297-3307. ISSN 0165-5701

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Abstract

Purpose: Excessive accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) increases resistance to the outflow of aqueous humor, which inevitably contributes to the elevation of intraocular pressure (IOP) in primary open angle glaucoma (POAG). Endothelin 1 (ET-1), a potent vasoconstrictor peptide, is reported to enhance profibrotic processes in multiple organs like liver, lung, and kidney tissues, which also significantly increases aqueous humor in POAG patients. Here we tested the hypothesis that ET-1 plays a key role in excessive accumulation in the trabecular meshwork and increase in IOP.
Methods: To test the effect of ET-1 on expression of fibronectin (FN), collagen type IV (COL-IV) and its receptor pathway, cultured human TM cells (HTMCs) were treated with ET-1, ET-1+ ETAR antagonist (BQ123) or ETBR antagonist (BQ788). The protein expression levels of FN, and COL-IV were evaluated by western-blot. A time course effect of ET-1 on the transcription level of the connective tissue growth
factor (CTGF) was investigated by qRT-PCR. Next, we down regulated the transcription level of CTGF by its antisense oligodeoxynucleotide sequence and then tested the expression levels of FN, and COL-IV. Lastly, we observed the effect of ET1 on IOP changes, expression of FN, and COL-IV in an ex-vivo model of cultured anterior eye segment.
Results: In cultured HTMs, the expression of FN and COL-IV was significantly increased after ET-1 treatment, and this could be blocked by ETAR antagonist (BQ123) but not ETBR antagonist (BQ788). Further, the CTGF mRNA level also
increased significantly and reached the top level at 48h after ET-1 treatment. However, the induced ET-1 increased the expression of FN and COL-IV in HTMCs and could be reversed by the downregulation of CTGF. In an ex-vivo model,
incensement of FN and COL-IV expression were observed too after ET-1 perfusion. Furthermore, IOP significantly increased after ET-1 administration. Nevertheless, this could be decreased by the ETAR antagonist (BQ123) but not the ETBR antagonist (BQ788).
Conclusions: These results indicate that ET-1 in aqueous humor could lead to the abnormal synthesis of FN and COL-IV via the ETA-CTGF pathway which could result in the accumulation of ECM in trabecular meshwork and incensement of IOP.

Item Type:	Article
Identifier:	10.1007/s10792-023-02733-y
Additional Information:	This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record will be available online at: https://www.springer.com/journal/10792
Keywords:	glaucoma, endothelin-1, trabecular meshwork, fibronectin, collagen type IV
Subjects:	Medicine and health > Clinical medicine
Related URLs:	Publisher Publisher
Depositing User:	Anne Manyande
Date Deposited:	24 Apr 2023 17:35
Last Modified:	21 Apr 2024 02:45
URI:	https://repository.uwl.ac.uk/id/eprint/9942

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