Abstract
Purpose :
Diabetic retinopathy is the leading cause of blindness in working age adults with limited therapies available. Gene deletion studies revealed norrin is required for formation and maintenance of the blood retinal barrier (BRB). Studies also revealed norrin can reverse vascular endothelial growth factor (VEGF) or diabetes-induced permeability. In this study we explored the ability of norrin treatment to prevent diabetes induced loss of visual function. We hypothesize that norrin will prevent vascular permeability and preserve visual function in a rat model of diabetes.
Methods :
Diabetes was induced by streptozotocin (STZ) in adult male Long-Evans rats. Visual acuity and contrast sensitivity were measured by assessing optokinetic response using OptoMotry™. Electroretinogram (ERG) was measured using a Celeris ERG. Retinal structure was analyzed by optical coherence tomography (OCT). To test the effect of norrin treatment. Rats were injected intravitreally with norrin (40ng/eye) every two weeks starting at 2 or 6 weeks after the onset of diabetes. Visual function was assessed at baseline, after 6 and 12 weeks of diabetes. Permeability was assessed after FITC-BSA perfusion and albumin immunostaining. Changes in norrin and related protein content were determined by Western blot and mRNA by RT-PCR.
Results :
Visual acuity and contrast sensitivity were significantly reduced by 2 months of diabetes and further reduced at 5 months of diabetes. Western blotting revealed a significant 50% loss of norrin protein in diabetic rats at both 2 and 5 months of diabetes. No structural changes were observed after 3 months of diabetes and limited changes in ERG were observed. Visual acuity and contrast sensitivity were preserved in diabetic rats following norrin treatment initiated at 2 weeks after diabetes but not when initiated at 6 weeks. Diabetes-induced retinal permeability was blocked in animals treated with norrin at 2 weeks after onset of diabetes.
Conclusions :
Loss of visual function was associated with reduction of norrin protein expression in diabetic rats. Replacing norrin through repeat intravitreal injection prevented vascular permeability and preserved visual function in this model of diabetes. These results reveal norrin replacement stabilizes the BRB in diabetes and preserves visual function. These studies provide support for developing novel therapeutic options that promote norrin signaling as potential new treatments for diabetic retinopathy.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.