Effects of the glucagon-like peptide-1 receptor agonist liraglutide on retinal endothelial function and oxidative stress during sepsis.

PURPOSE: To test the hypothesis that the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide improves retinal vascular function in mice with polymicrobial sepsis. METHODS: Three groups of mice were studied. Two groups underwent cecal ligation and puncture to induce polymicrobial sepsis. One received vehicle and the other liraglutide via intraperitoneal injection starting 24 h before the procedure and continuing twice daily until euthanasia. A third group underwent sham surgery and served as control. Forty-eight hours after sepsis induction, mice were euthanized and retinas were isolated for assessment of vascular function by videomicroscopy. In addition, reactive oxygen species (ROS) formation and gene expression were evaluated using dihydroethidium staining, quantitative real-time PCR, and immunostaining of NADPH oxidase (NOX)1 and NOX2, respectively. RESULTS: Endothelium-dependent vasodilation to acetylcholine was markedly impaired in retinal arterioles of septic, vehicle-treated mice but was partially preserved in liraglutide-treated septic mice. In contrast, vasodilation to the endothelium-independent vasodilator sodium nitroprusside was similar across all groups. Dihydroethidium staining revealed increased ROS signals in retinal arterioles, the ganglion cell layer, the inner and outer nuclear layers, and the optic nerve of septic, vehicle-treated mice. These increases were attenuated by liraglutide treatment. Furthermore, retinal mRNA expression of NOX1 was significantly upregulated in septic, vehicle-treated mice but remained at control levels in liraglutide-treated septic mice. . In addition, mRNA levels of SOD2, nNOS, and PAI-1 were increased, whereas NOX4, COX-2, and UCP-2 were decreased in septic, vehicle-treated mice. Liraglutide treatment was associated with increased mRNA expression for the antioxidant enzymes SOD1 and SOD3, reduced expression for MCP-1, ICAM-1 and PAI-1 mRNA levels and restoration of UCP-2 mRNA expression. Immunoreactivity for NOX1, but not NOX2, was increased in retinal blood vessels of septic mice. CONCLUSION: Treatment with liraglutide attenuates endothelial dysfunction, reduces oxidative stress, and suppresses NOX1 upregulation in the retina during polymicrobial sepsis. These findings highlight the preventive and therapeutic potential of GLP-1 receptor agonists for retinal vascular complications associated with sepsis and systemic inflammation.