Retinoid x receptor modulation protects against ER stress response and rescues glaucoma phenotypes in adult mice

Retinoid X receptors (RXRs) play an important role in transcription, are involved in numerous cellular networks from cell proliferation to lipid metabolism and are essential for normal eye development. RXRs form homo or heterodimers with other nuclear receptors, bind to DNA response elements and regulate several biological processes including neurogenesis. Mounting evidence suggests that RXR activation by selective RXR modulators (sRXRms) may be neuroprotective in the central nervous system. However, their potential neuroprotective role in the retina and specifically in glaucoma remains unexplored. This study investigated changes in RXR expression in the human and mouse retina under glaucomatous stress conditions and investigated the effect of RXR modulation on the RGCs using pharmacological approaches. RXR protein levels in retina were downregulated in both human glaucoma and experimental RGC injury models while RXR agonist, bexarotene treatment resulted in upregulation of RXR expression particularly in the inner retinal layers. Retinal electrophysiological recordings and histological analysis indicated that inner retinal function and retinal laminar structure were preserved upon treatment with bexarotene. These protective effects were associated with downregulation of ER stress marker response upon bexarotene treatment under glaucoma conditions. Overall, retinal RXR modulation by bexarotene significantly protected RGCs in vivo in both acute and chronic glaucoma models.