Abstract
Purpose :
Our previous studies showed the protective effects of Angiotensin-(1-7) in animal models of diabetic retinopathy (DR) and ocular inflammation. Our recent effort to identify downstream targets of Ang-(1-7) signaling has discovered that Ang-(1-7) increased the expression of OPA1, an inner mitochondrial membrane protein essential for mitochondrial fusion. OPA1 is also emerging as a central regulator of mitochondrial quality control, apoptosis, calcium signaling, mitochondrial DNA stability, and metabolism. Since mitochondrial dysfunction is implicated in pathogenesis of DR, we hypothesize that OPA1 expression maybe reduced in diabetic retina and reduced OPA1 expression may contribute to development and progression of DR. To test this hypothesis we examined OPA1 expression in different time points of diabetic animals as well as human donor eyes from with or without DR.
Methods :
Age-matched non-diabetic and streptozotocin (STZ) induced diabetic eNOS-/- mice were used. Human donor eyes with or without DR were procured from Lions Eye Institute. OPA1 expression in mouse and human retina was examined by immunofluorescence using OPA1 specific antibody and the mRNA level was analyzed by real-time RT-PCR and protein expression by Western blotting.
Results :
OPA1 is expressed in the retinal ganglion cells (RGCs) more abundant than other cell types in the retina, consistent with previous reports. Diabetic eNOS-/- mouse retina displayed a significantly reduced expression of OPA1. Reduced OPA1 expression was detected as earlier as 7 days after STZ-induced diabetes. There was > 50% reduction in OPA1 expression at 2 month after induced diabetes, correlated with significantly reduced number of mitochondria (>30% reduction) and altered mitochondrial ultrastructure in the RGC layer. The OPA1 expression was 2.5 fold lower in the human donor retina with DR as compared to non-diabetic donors.
Conclusions :
Diabetes resulted in reduced OPA1 expression and mitochondrial dysfunction in eNOS-/- mouse retina and human donor eyes. Reduced OPA1 expression occurs earlier in diabetes. These results suggest that OPA1 and mitochondrial dynamics may play an important role in the pathogenesis of DR and may be a novel target for therapeutic intervention.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.