Liraglutide preserves retinal endothelial function and reduces oxidative stress in septic mice

Patients with sepsis often experience systemic inflammation and microvascular dysfunction, which can extend to the retina, potentially leading to vision impairment. Current treatments for sepsis primarily focus on infection control and supportive care, but specific therapies to protect delicate microvasculature, like that in the retina, are lacking. Oxidative stress is a key driver of endothelial dysfunction in sepsis. Glucagon-like peptide-1 (GLP-1) receptor agonists, like liraglutide, are known for their metabolic benefits but are increasingly recognized for anti-inflammatory and vascular protective properties, making them a candidate for mitigating sepsis-induced retinal damage.

Researchers investigated the effects of liraglutide on retinal vascular function and oxidative stress in a mouse model of polymicrobial sepsis. Three groups of mice were studied: a sham control, a septic vehicle-treated group, and a septic liraglutide-treated group. Sepsis was induced via cecal ligation and puncture. Liraglutide was administered via intraperitoneal injection starting 24h before the procedure and continuing twice daily until euthanasia. Forty-eight hours post-sepsis induction, retinas were isolated for ex vivo videomicroscopy to assess endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilation. Dihydroethidium staining quantified reactive oxygen species (ROS) formation, while quantitative real-time PCR and immunostaining evaluated gene expression of NADPH oxidase (NOX)1 and NOX2 and other markers.

Endothelium-dependent vasodilation to acetylcholine was markedly impaired in retinal arterioles of septic, vehicle-treated mice. However, this impairment was partially preserved in liraglutide-treated septic mice. In contrast, vasodilation to the endothelium-independent vasodilator sodium nitroprusside was similar across all groups, indicating a specific effect on endothelial function. Dihydroethidium staining revealed increased ROS signals in retinal arterioles, the ganglion cell layer, inner and outer nuclear layers, and the optic nerve of septic, vehicle-treated mice. These ROS 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. mRNA levels of SOD2, nNOS, and PAI-1 were increased, while 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.