Protective effect of trans-resveratrol against excitotoxic retinal injury: Focus on renin-angiotensin system and adenosine interaction.

Abstract

NMDA-mediated excitotoxic retinal injury, altered renin-angiotensin system (RAS) expression and adenosine receptor (AR) signaling are associated with glaucomatous retinal ganglion cells loss. Trans-resveratrol protects against NMDA-induced retinal injury via adenosine receptors. It also alters RAS expressions in relation to cardiovascular functions. However, the mechanistic links among these pathways remain unclear. We hypothesized that the protective effect of trans-resveratrol against NMDA-induced retinal excitotoxicity involves AR mediated regulation of RAS expression. Using a oculonormotensive rat model of NMDA-induced retinal injury, we examined the retinal RAS expression following NMDA exposure with or without trans-resveratrol pre-treatment. To delineate the contribution of AR, effect of trans-resveratrol on retinal RAS expression was studied in the presence of selective adenosine A1 and A2A antagonists. The angiotensinogen, angiotensin II and angiotensin II type 1 receptor expressions were significantly lower in trans-resveratrol pre-treated compared to NMDA-treated group (p&#xa0;<&#xa0;0.0001). However, the renin expression was significantly greater in trans-resveratrol pre-treated compared to NMDA-treated group (p&#xa0;<&#xa0;0.05). The alternate RAS proteins including ACE2 and Ang (1-7) showed significantly greater expressions in trans-resveratrol pre-treated compared to NMDA-treated group (p&#xa0;<&#xa0;0.0001). Overall, trans-resveratrol shifts RAS towards a more active alternate rather than the classical arm. In alignment with these observations, TUNEL staining showed a significantly reduced apoptotic cell count in the ganglion cell layer (GCL) in trans-resveratrol pre-treated compared to NMDA treated group (p&#xa0;<&#xa0;0.01). Morphological observations showed that it protects against NMDA-induced loss of GCL thickness within inner retina and retinal cell density in GCL (p&#xa0;<&#xa0;0.01). These effects of trans-resveratrol were abolished by pre-treatment with adenosine A1 but not by A2A receptor antagonist highlighting the role of adenosine-RAS interactions via adenosine A1 receptors in the neuroprotective effect of trans-resveratrol. This study not only clarifies mechanisms underlying the neuroprotective effects of trans-resveratrol but for the first time provides novel insight into adenosine-RAS interactions, which may be explored as potential targets for therapeutic intervention in neurodegenerative conditions.