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 (RGC) resulting in irreversible vision loss. Our previous work demonstrated that irbesartan, an angiotensin II type I receptor (AT1R) blocker (ARB), promotes RGC survival in rat retinal explants. This study extends these findings to ex-vivo mouse explants, in-vivo optic nerve crush (ONC) model, and transcriptomic analysis to identify associated pathways. Retinal explants from C57BL/6 mice were cultured for four days with irbesartan (10μM), vehicle, or angiotensin II (2μM). RGC survival assessed by βIII-tubulin and RNA-binding protein with multiple splicing (RBPMS) immunostaining; superoxide and mitochondrial density were measured using dihydroethidium (DHE) and MitoTracker Red CMXRos. Mice received vehicle or irbesartan (10μM) eye drops for seven days after ONC 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 DHE intensity (p < 0.0072) and preserved mitochondrial labelling at day 2 (p = 0.02). RNA-sequencing revealed differential expression of electron transport chain (ETC) genes (e.g., Cox4i2, Ndufa12), with gene set enrichment analysis (GSEA) 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.