Abstract
Purpose :
The long delay (years) between the onset of diabetes (DM) and development of diabetic retinopathy (DR) does not align with our current understanding of DR pathogenesis, which includes hyperglycemia (HG)-driven increased oxidative stress that rapidly triggers progressive and irreversible mitochondrial dysfunction. An explanation for this dissonance is the existence of an endogenous system that protects the retina from DM-induced damage. To consider this possibility, we developed experimental approaches to search for a DM-triggered protective system and used it to test if it exists in the retinal vasculature of a mouse model of DR
Methods :
C57Bl6J male mice were made diabetic by injecting them with streptozotocin. Death of cells within retinal vessels was induced by exposing enucleated eye to oxidative stress (tert-butyl hydroperoxide). The dose and duration of the oxidative stress were chosen to induce a readily detectable level of death of cells within the retinal vessels of non-DM mice. To detect cell death, the retinal vasculature was isolated and stained with TUNEL and DAPI. Five to eight randomly selected peri-optic regions were photographed, and the number of TUNEL/DAPI double-positive cells was counted and normalized for the area. A set consisted of a pair of eyes from randomly selected non-DM and DM mice that were processed in parallel.
Results :
DM-induced protection of the retinal vessels from oxidative stress-induced death. More specifically, less cells died in the retinal vessels of DM mice as compared with non-DM controls. The highest level of protection (100% and 83%) was observed during the period of DM prior to any reported retinal abnormalities (5 and 8 days of DM). Other groups have reported that the earliest signs of neural dysfunction commence at 14 days, and we observed that protection had fallen to 20% at the 15-day time point. As the duration of DM was extended to 28 days, protection remained low (20%) and vulnerability (increased death in DM as compared with non-DM) appeared at a level of 20%.
Conclusions :
These observations reveal the existence of a previously unappreciated DM-triggered system that protects cells within retinal vessels from the deleterious effects of DM. Preservation or extension of endogenous protection is a novel therapeutic strategy to indefinitely delay DR, which would complement the current approaches the mitigate symptoms in people who have already developed DR.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.