FOXO1 plays an important role in enhanced microvascular cell apoptosis and microvascular cell loss in type 1 and type...

Area of Science:

• Ophthalmology
• Endocrinology
• Molecular Biology

Background:

• Diabetic retinopathy (DR) is a leading cause of vision loss.
• Microvascular cell loss is a key pathological feature of DR.
• Early events driving this cell loss remain incompletely understood.

Purpose of the Study:

• To investigate the role of Forkhead box protein 1 (FOXO1) in early microvascular cell loss in diabetic retinopathy.
• To elucidate the mechanisms by which high glucose affects FOXO1 activity and subsequent retinal cell damage.

Main Methods:

• In vivo studies in streptozotocin-induced diabetic rats and Zucker diabetic fatty rats.
• In vitro experiments using rat microvascular endothelial cells (RMECs) exposed to high glucose.
• Assessment of FOXO1 DNA binding activity, nuclear translocation, and phosphorylation.
• Inhibition of FOXO1 using small-interfering RNA (siRNA) and tumor necrosis factor (TNF)-alpha blockers.
• Measurement of microvascular cell apoptosis, pericyte ghosts, and acellular capillaries.

Main Results:

• Elevated FOXO1 DNA binding and nuclear translocation were observed in diabetic rat retinas, reduced by TNF inhibition.
• FOXO1 inhibition via siRNA significantly reduced high-glucose-induced apoptosis, pericyte ghost formation, and acellular capillaries in RMECs.
• High glucose decreased FOXO1 phosphorylation and Akt phosphorylation in RMECs, with FOXO1 activation mediated by TNF-alpha and reactive oxygen species (ROS).

Conclusions:

• FOXO1 plays a critical role in retinal microvascular cell loss in both type 1 and type 2 diabetes models.
• High glucose activates FOXO1, contributing to retinal microvascular damage.
• Targeting FOXO1 presents a potential therapeutic strategy for mitigating diabetic retinopathy progression.