Abstract
Purpose :
Complete loss of Glut1 (Slc2a1) from retinal cells, or specifically in rod photoreceptors, leads to retinal degeneration due to arrested development of rod outer segments and rod photoreceptor death. However, loss of only 1 Glut1 allele in retinal cells (driven by Crx-cre mediated recombination) initiates a reduction, but not absence of Glut1 in the retina and yields no overt phenotype. Importantly, when these retina-specific Glut1 conditional knockdown (Ret-Glut1 CKD) mice were made diabetic, they were resistant to retinal dysfunction, inflammation/oxidative stress, and polyol accumulation. The goal of the present study is to determine if the protection was garnered by Glut1 reduction specifically in the rod photoreceptor cells.
Methods :
Rod-specific Glut1 conditional knockdown (Glut1flox/+RhoiCre+; i.e., Rho-Glut1 CKD) mice were generated by crossing transgenic mice expressing Rho-iCre (B6.Cg-Pde6b+ Tg(Rho-icre)1Ck/Boc, The Jackson Laboratory, # 015850) with mice carrying floxed alleles for Slc2a1 (The Jackson Laboratory, #031871). Structure and function were assessed by electroretinography (ERGs), immunohistochemistry (IHC), and qPCR to determine changes in the retinas of control and diabetic mice.
Results :
Rho-Glut1 CKD mice displayed normal retinal morphology and function through 6 months of age. At 1 year of age, reduced ERGs were observed, as compared to littermate controls. Five consecutive, daily streptozotocin injections induced diabetes in 6-8 week old control and Rho-Glut1 CKD littermate mice. Following 4 weeks of hyperglycemia, decreased ERG amplitudes in the a-wave, b-wave and c-wave were identified in control mice. Light evoked responses in diabetic Rho-Glut1 CKD mice were ameliorated. Analysis of later timepoints, development of inflammation and oxidative stress and morphology are on-going.
Conclusions :
The retina is critically reliant on glucose for proper function and survival; however, a targeted, moderate reduction of Glut1 in rod photoreceptors in a diabetic environment may be considered as a therapeutic intervention for the prevention of diabetic retinopathy.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.