Early vascular damage precedes neuronal impairment in experimental pre-diabetic retinopathy

Background Diabetic retinopathy (DR) is the most common microvascular complication of prolonged hyperglycemia, leading to both vascular and neuronal damage in the retina. However, the precise timeline of vascular and neuronal damage remains a subject of ongoing debate. Recent studies have suggested that retinopathy may occur during the pre-diabetic stage, even before the onset of overt diabetes. In this study, we characterized a mouse model deficient in nucleoside diphosphate kinase B (NDPKB) as pre-diabetic retinopathy and investigated the development of retinal vascular and neuronal damage.

Material and methods Glucose tolerance test (GTT) and insulin tolerance test (ITT) were conducted on 8-month-old NDPKB deficient mice. Retinal morphometry was performed using retinal digest preparations from 4- and 5-month-old mice. Electroretinography (ERG) and optical coherence tomography (OCT) were carried out at 5 and 18 months. Protein expression and localization were assessed through immunoblotting and immunofluorescence staining.

Results NDPKB-/- mice exhibited comparable body weight and blood glucose levels to wild-type controls. GTT showed impaired glucose tolerance, while no differences were observed in the ITT between the groups, suggesting that NDPKB mice represent a pre-diabetic mouse model. In NDPKB deficient retinas, a significant downregulation of vascular endothelial cadherin (VE-cadherin) was observed in the 4-month-old mice, with a further decrease at 5 months. Whole-mount immunofluorescence staining demonstrated a notable reduction in VE-cadherin expression within the deep capillary layer, while retinal arteries and veins remained unaffected. Interestingly, pericyte loss was evident in the 5-month-old retinas, with no significant pericyte loss at 4 months, indicating an early onset of vascular damage in the NDPKB deficient retinas. No significant changes were detected in ERG responses in the 5-month-old NDPKB retinas. However, unexpectedly, 18-month-old NDPKB deficient mice exhibited significant alternations in ERG amplitude and retinal thickness, suggesting impaired retinal function.

Conclusion Our study revealed that NDPKB deficient mice serve as an effective model for pre-diabetic retinopathy, exhibiting VE-cadherin reduction and pericyte loss in the early stage, followed by neuronal impairment in the later stage. These findings indicate that vascular damage occurs prior to neuronal impairment in the progression of pre-diabetic retinopathy.

Publication History

Article published online:
28 May 2025