Abstract
Purpose :
Diabetic retinopathy (DR) is one of the leading causes of blindness in the modern world and is associated with alterations in retinal vasculature and photoreceptor function, the health of which is largely maintained by the retinal pigment epithelium (RPE). However, the contribution of RPE in the pathogenesis of DR is rarely studied. AKT plays an important role in RPE cell survival, glucose metabolism, and apoptosis. This study investigates the potential role of AKT2 (an isoform of AKT) in RPE cells in DR pathogenesis
Methods :
We generated Best1 (AKT2) constitutive knock-in (KI) and AKT2 conditional knockout (cKO) mice. Diabetes (D) was induced in wild type (WT), AKT2 cKO and AKT2 KI mice by IP injection of streptozotocin for 5 consecutive days. Electroretinograms (ERGs) were performed 2 months after induction of diabetes (4 months of age), while rodent body weights and blood glucose levels were monitored throughout. Mice were sacrificed at 2 months of diabetes (4 months of age) and then HbA1c and expression of inflammatory proteins were measured.
Results :
Blood glucose and HbA1c were elevated in diabetic WT, AKT2 KI, AKT2 floxed and AKT2 cKO mice. WT diabetic mice exhibited significant reductions in a-, b-, and c wave amplitudes (58 ± 23V, 125 ± 26V, 129 ± 43V) compared to WT non-diabetic (N) controls. Similar results were seen in AKT2 floxed diabetic mice. The diabetes-induced defects were not seen in AKT2 cKO mice (192±11V, 348±34V, 199±46V), while AKT2 KI exhibited similar reduction as shown in WT-D. There were no significant changes in the ERGs among animals assigned to N groups. Expression of the retinal inflammatory protein ICAM1 was increased 1.51 fold (p=0.01) in WT-D mice as compared to WT-N mice; it was further increased in AKT2 KI-D mice, however in AKT2 cKO mice, the diabetes-induced elevation of ICAM1 was decreased relative to AKT2 floxed N.
Conclusions :
Deletion of AKT2 in RPE cells prevents diabetes-induced defects in RPE (c-wave), further protecting inner retinal cell function (a-, b wave). The retinal protective effect observed in AKT2 cKO diabetic mice may work through the downregulation of retinal inflammation (ICAM1) induced by diabetes.
This is a 2020 ARVO Annual Meeting abstract.