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

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.

Epithelial-mesenchymal transition; Lysyl oxidase-like 2; Neovascular age-related macular degeneration; Retinal pigment epithelium; Subretinal fibrosis.