Complement C3/C3aR Signaling Pathway Inhibition Ameliorates Retinal Damage in Experimental Retinal Vein Occlusion

Retinal vein occlusion (RVO) is a common retinal vascular disease that severely threatens visual function. This study aims to elucidate the role of the complement C3/C3aR signaling pathway in a laser-induced RVO mouse model and to explore its potential as a therapeutic target.

RVO was induced in C57BL/6J mice using laser photocoagulation combined with photosensitizer dye administration. Two days later, retinal tissues were collected for bulk RNA sequencing. The activation of the C3/C3aR signaling pathway was validated through RT-qPCR and Western blot. The C3aR antagonist SB290157 (C3aRA) was administered intravitreally and retinal morphological and functional changes were examined 1, 2, and 8 days later by optical coherence tomography (OCT), fundus photography (FP), and fluorescein angiography (FA), optomotor response (OKR) test, and electroretinogram (ERG).

RVO mice exhibited marked increases in retinal thickness (P < 0.001) and fluorescence leakage (P < 0.01) compared to the sham-laser group. Bulk RNA-seq revealed significant upregulation of the complement pathway. Elevated expression of C3 and C3aR (P < 0.05) was confirmed by RT-qPCR and Western blot. Blocking C3aR with SB290157 significantly alleviated RVO-induced retinal edema, vascular leakage, and structural damage. Functional assessment showed that SB290157 treatment significantly improved contrast sensitivity (P < 0.05), increased b-wave (P < 0.001), and oscillatory potentials (Ops) amplitudes (P < 0.05) in RVO mice. RNA-seq analysis demonstrated that SB290157 significantly reduced the inflammatory mediator-related pathways and upregulated visual perception pathways (P < 0.05).

The complement C3/C3aR signaling pathway is critically involved in RVO-induced retinal damage and targeting this pathway may be a promising approach for RVO treatment.