Abstract
Purpose :
Diabetic retinopathy is a leading cause of irreversible vision loss. Vascular endothelial growth factor-B (VEGFB) inhibition has shown promise as a potential treatment in animal models of type II diabetic kidney disease. Here, we examined whether targeting VEGFB has utility in reducing retinal changes in a rat model of type I diabetes.
Methods :
Sprague-Dawley rats (N=37) were rendered diabetic with a single injection of streptozotocin (STZ; 50mg/kg) and treated weekly with either a vehicle (BM4; 20mg/kg; i.p) or an antibody targeting VEGFB (2H10; 20mg/kg; i.p) for 12 weeks. Non-diabetic rats (N=17) received citrate buffer and were treated weekly with the vehicle (BM4). Following 12 weeks, animals underwent evaluation of retinal structure and function (OCT and twin-flash electroretinography), were killed and their retinae collected for whole retina bulk RNAseq, quantitative PCR or fixed for 30 minutes in paraformaldehyde for histological assessment. Retinae from C57Bl6 mice were cultured for 24 hours in either high (25mM) or normal glucose (6mM) in the presence of vehicle (BM4) or anti-VEGFB (2H10) and underwent lipidomic analysis.
Results :
VEGFB was highly expressed in retinal Müller cells and its receptor, VEGFR1, was localized to photoreceptor and bipolar cell terminals. Twelve weeks following the induction of diabetes, increased expression of both VEGFB and VEGFR1 was accompanied by significant reductions in photoreceptor function as well as downregulation in genes associated with major metabolic pathways. In addition, there was upregulation in genes associated with inflammation/innate immunity and angiogenesis. Treatment with anti-VEGFB abrogated the loss in photoreceptor function in male rats, and normalized the changes in gene expression in many gene sets including fatty acid metabolism and ATP synthesis. In addition, glucose-induced changes in lipids, including phosphatidylethanolamines and cardiolipins, were attenuated by treatment with anti-VEGFB, highlighting potential regulation of mitochondrial function.
Conclusions :
Our results suggest that diabetes is associated with altered VEGFB signaling and that treatment targeting VEGFB reduces some effects of diabetes in the retina. Notably, lipid and fatty acid metabolism were altered by diabetes and abrogated by treatment. These results highlight a novel way to reduce early retinal changes during diabetes.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.