Irbesartan Promotes Retinal Ganglion Cell Survival and Modulates Mitochondrial and Inflammatory Pathways in Mouse Retinal Explant and in Optic Nerve Crush Models

Glaucoma is a neurodegenerative eye disease characterized by progressive loss of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Previous work demonstrated that irbesartan, an angiotensin II type I receptor blocker, promotes RGC survival in rat retinal explants. This study extends these findings to ex vivo mouse explants, in vivo optic nerve crush model, and transcriptomic analysis to identify associated pathways. Retinal explants from C57BL/6 mice were cultured for 4 days with irbesartan (10 μmol/L), vehicle, or angiotensin II (2 μmol/L). RGC survival was assessed by βIII-tubulin and RNA-binding protein with multiple splicing (RBPMS) immunostaining; superoxide and mitochondrial density were measured using dihydroethidium and MitoTracker Red CMXRos. Mice received vehicle or irbesartan (10 μmol/L) eye drops for 7 days after optic nerve crush to assess RGC survival. Irbesartan enhanced RGC survival in explants (1.5-fold and 4-fold; P = 0.0138 and 0.000129) and in vivo (1.7-fold; P = 0.0045). Irbesartan reduced dihydroethidium intensity (P < 0.0072) and preserved mitochondrial labeling at day 2 (P = 0.02). RNA sequencing revealed differential expression of electron transport chain genes (eg, Cox4i2 and Ndufa12), with gene set enrichment analysis showing enrichment of proinflammatory pathways in vehicle-treated explants and neuronal/metabolic pathways with irbesartan. In conclusion, irbesartan reduces oxidative stress and modulates mitochondrial and inflammatory pathways, potentially supporting RGC survival, thus providing insights relevant to glaucoma and optic neuropathies involving RGC degeneration.