Akt2 signaling in RPE contributes to retinal fibrosis in DR

Abstract

Purpose : Diabetic Retinopathy (DR) is a significant complication of diabetes that cause blindness in adults. Retinal fibrosis has been shown to be closely associated with the development of proliferative DR, and clinical studies have shown that fibrotic membranes exhibit uncontrolled growth in PDR and contribute to retinal detachment from RPE cells, ultimately leading to vision loss. While anti-VEGF agents and invasive laser treatments serve as the primary treatment for PDR, retinal fibrosis is another confounding factor that has received minimal attention for potential therapeutic strategies. Therefore, further clinical and basic studies are necessary and critical to provide evidence of how retinal fibrosis contributes to DR and to develop potential interventions to treat retinal fibrosis in DR. This study investigates the potential role of Akt2 in the diabetes-induced fibrosis in RPE cells.

Methods : Best1-Cre generated RPE-specific Akt2 conditional knockout (cKO) mice were used. Rodent body weights and blood glucose levels were monitored while diabetes was induced in Akt2^fl/fl and Akt2 cKO mice by intraperitoneal injection of Streptozotocin for 5 consecutive days. The mice were sacrificed after an 8 month duration of diabetes (10 months of age), and HbA1c, tight junction proteins, and epithelial-mesenchymal transition (EMT) markers and fibrosis markers were examined.

Results : Blood glucose and HbA1c were elevated in diabetic Akt2^fl/fl and Akt2 cKO mice. Akt2^fl/fl and Akt2 cKO diabetic mice exhibited significantly lower body weights than appropriate non-diabetic controls. Knocking out Akt2 in RPE attenuated diabetes-induced increase of fibrosis markers in RPE, including collagen IV, CTGF, fibronectin and alpha-SMA. Diabetes-induced reduction of the RPE tight junction protein ZO-1 and adherens junction proteins occludin and E-cadherin were also rescued in Akt2 cKO diabetic mice; Both RNA and protein levels of the EMT markers SNAIL/SLUG and TWIST were elevated in the RPE cells of Akt2^fl/fl diabetic mice compared to non-diabetic control mice, while such alterations were inhibited in Akt2 cKO diabetic mice.

Conclusions : Deletion of Akt2 in the RPE may attenuate diabetes-induced retinal fibrosis.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.