Abstract
Purpose :
Evidence suggests that cells from the outer retina play an important role in the pathogenesis of diabetic retinopathy (DR), but whether or not the visual cycle activity is subnormal in diabetes, and whether decreasing or not that activity is a therapeutic approach to inhibit DR is controversial. Here we used the Lecithin:retinol acyltransferase (Lrat) knockout mice to investigate the effects of visual cycle inhibition on the development of early DR.
Methods :
Diabetes was induced in male C57Bl/6J (WT) and Lrat heterozygous (Lrat+/-) and homozygous (Lrat-/-) mice using streptozotocin. Retinoid metabolism, and biochemical and physiological abnormalities in the retina were evaluated at 2 months of diabetes using published methods. Vascular histopathology, permeability and retinal thickness were evaluated at 8 months of diabetes. Non-retinal effects of inhibition of the visual cycle were examined in leukocytes ex vivo at 2- and 8-months of diabetes.
Results :
At 2-months of diabetes visual function assessed by OKT and ERG was not significantly affected by diabetes or Lrat+/- whereas in Lrat-/- was severely attenuated. Rhodopsin levels in WT and Lrat+/- diabetics were similar to corresponding values of 11-cis-retinal as determined by retinoid analyses when compared to WT nondiabetics. Lrat+/- mice differed in their level of all-trans-retinyl esters by 50% less when compared to WT and diabetes had no influence in the total levels. No all-trans-retinyl esters were detected in the Lrat-/- groups. Diabetes-induced increase in retinal superoxide was significantly inhibited in Lrat+/- and Lrat-/- diabetic mice when compared to WT diabetics. At 8-months of diabetes, thickness of the ONL by OCT was similar between WT and Lrat+/- but Lrat-/- showed total loss of photoreceptors. Degeneration of retinal capillaries was significantly inhibited in Lrat+/-. Similar trends were apparent in diabetic Lrat-/- mice, but mortality in this group precluded further evaluation. The diabetes-induced increase in retinal vascular permeability was inhibited in the inner plexiform and inner nuclear layers of Lrat+/-mice, but not in the outer plexiform layer. The leukocyte-mediated cytotoxicity against retinal endothelial cells at 2- and 8-months of diabetes was inhibited in Lrat+/- and Lrat-/- mice when compared to WT diabetic mice.
Conclusions :
Lrat+/- diabetic mice are protected from the development of retinal vascular pathology in early DR.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.