4.7 Article

Soluble very low-density lipoprotein receptor (sVLDLR) inhibits fibrosis in neovascular age-related macular degeneration

Journal

FASEB JOURNAL
Volume 35, Issue 12, Pages -

Publisher

WILEY
DOI: 10.1096/fj.202101334R

Keywords

fibrosis; macular degeneration; TGF-beta signaling pathway; very low-density lipoprotein receptor; Wnt signaling pathway

Funding

  1. National Institutes of Health (NIH) [EY019309, EY012231, EY028949, EY032930, EY032931]
  2. Diabetic Animal Core and Histology and Image Core of diabetic COBRE [GM122744]
  3. NEI P30 [EY021725]

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The study suggests that sVLDLR plays an anti-fibrotic role in neovascular age-related macular degeneration (nAMD) by inhibiting the Wnt signaling pathway. Additionally, in human RPE cells, Wnt and TGF-beta signaling synergistically promote fibrosis.
Subretinal fibrosis is a key pathological feature in neovascular age-related macular degeneration (nAMD). Previously, we identified soluble very low-density lipoprotein receptor (sVLDLR) as an endogenous Wnt signaling inhibitor. This study investigates whether svLDLR plays an anti-fibrogenic role in nAMD models, including Vldlr(-/-) mice and laser-induced choroidal neovascularization (CNV). We found that fibrosis factors including P-Smad 2/3. alpha-SMA, and CTGF were upregulated in the subretinal area of Vldlr(-/-) mice and the laser-induced CNV model. The antibody blocking Wnt co-receptor LRP6 significantly attenuated the overexpression of fibrotic factors in these two models. Moreover, there was a significant reduction of sVLDLR in the interphotoreceptor matrix (IPM) in the laser-induced CNV model. A transgenic strain (sVLDLR-Tg) with sVLDLR overexpression in the IPM was generated. Overexpression of sVLDLR ameliorated the profibrotic changes in the subretinal area of the laser-induced CNV model. In addition, Wnt and TG F-beta signaling synergistically promoted fibrogenesis in human primary retinal pigment epithelium (RPE) cells. CRISPR/Cas9-mediated LRP6 gene knockout (KO) attenuated this synergistic effect. The disruption of VLDLR expression promoted, while the overexpression of sVLDLR inhibited TGF-beta-induced fibrosis. These findings suggest that overactivated Wnt signaling enhances the TGF-beta pathway in subretinal fibrosis. sVLDLR confers an antifibrotic effect, at least partially, through the inhibition of Wnt signaling and thus, has therapeutic potential for fibrosis.

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