Lysyl oxidase-like 2 inhibition alleviates subretinal fibrosis in neovascular age-related macular degeneration model

IF 2.7 2区医学 Q1 OPHTHALMOLOGY

Experimental eye research Pub Date : 2025-08-20 DOI:10.1016/j.exer.2025.110588

Xiaowei Yang , Anping Ma , Yuan Liu, Zhicheng He, Jianfeng Yu, Shu Su, Jia Chen, Aimin Sang

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引用次数: 0

Abstract

Subretinal fibrosis is a significant contributing factor to the irreversible vision loss linked with neovascular age-related macular degeneration (nAMD). Cellular senescence, a process implicated in the development of nAMD, has been suggested to promote fibrosis through epithelial-mesenchymal transition (EMT). LOXL2 (Lysyl oxidase-like 2) is associated with a variety of fibrotic conditions. However, the role of LOXL2 in subretinal fibrosis remains to be elucidated. In the study, we induced retinal pigment epithelium (RPE) senescence in vitro and in vivo. Further analysis showed that conditioned medium from senescent RPE upregulated the expression of mesenchymal and fibrogenic markers in pre-senescent RPE. LOXL2 silencing was found to attenuate RPE senescence and suppress conditioned medium induced EMT, which was associated with reduced oxidative stress and linked to the TGF-β1/p38 MAPK pathway. In vivo studies confirmed these findings, showing that systemic LOXL2 inhibition reduced D-galactose (D-gal) induced senescence and subretinal fibrosis following laser injury in mice. This treatment also partially corrected the redox imbalance and abnormal activation of TGF-β1/p38 MAPK pathway. The findings indicate that LOXL2 inhibition may be a promising therapeutic approach to prevent subretinal fibrosis in nAMD, providing a novel intervention strategy for a condition for which there are currently no effective treatments.

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赖氨酸氧化酶样2抑制减轻新生血管性年龄相关性黄斑变性模型视网膜下纤维化

视网膜下纤维化是与新生血管性年龄相关性黄斑变性（nAMD）相关的不可逆视力丧失的重要因素。细胞衰老，一个与nAMD发展有关的过程，已被认为通过上皮-间质转化（EMT）促进纤维化。LOXL2（赖氨酸氧化酶样2）与多种纤维化状况有关。然而，LOXL2在视网膜下纤维化中的作用仍有待阐明。在体外和体内诱导视网膜色素上皮（RPE）衰老。进一步的分析表明，来自衰老RPE的条件培养基上调了衰老前RPE中间充质和纤维化标志物的表达。研究发现，LOXL2沉默可减轻RPE衰老，抑制条件培养基诱导的EMT，这与氧化应激降低有关，并与TGF-β1/p38 MAPK通路有关。体内研究证实了这些发现，表明系统性LOXL2抑制可减少小鼠激光损伤后d -半乳糖（D-gal）诱导的衰老和视网膜下纤维化。该处理也部分纠正了TGF-β1/p38 MAPK通路的氧化还原失衡和异常激活。研究结果表明，LOXL2抑制可能是预防nAMD视网膜下纤维化的一种有希望的治疗方法，为目前尚无有效治疗方法的疾病提供了一种新的干预策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental eye research 医学-眼科学

CiteScore

6.80

自引率

5.90%

发文量

323

审稿时长

66 days

期刊介绍： The primary goal of Experimental Eye Research is to publish original research papers on all aspects of experimental biology of the eye and ocular tissues that seek to define the mechanisms of normal function and/or disease. Studies of ocular tissues that encompass the disciplines of cell biology, developmental biology, genetics, molecular biology, physiology, biochemistry, biophysics, immunology or microbiology are most welcomed. Manuscripts that are purely clinical or in a surgical area of ophthalmology are not appropriate for submission to Experimental Eye Research and if received will be returned without review.