Abstract
Purpose :
We recently demonstrated that loss of RPE-specific insulin receptor-mediated signal transduction did not have a significant impact on a- and b- wave amplitudes in the dark adapted electroretinogram (ERG) of diabetic mice. However, loss of RPE-specific insulin receptor-mediated signaling did appear to lead to lower relative c-wave values in diabetic animals. This result implies that insulin receptor-mediated signaling confers protection to RPE function in diabetes. Despite this finding, insulin signaling in the RPE has also been shown to induce HIF1α and oxidative stress. Although no changes were found in the dark adapted strobe flash ERG amplitudes, the development of oxidative stress and inflammation is often uncoupled from functional ERG defects in mouse models of diabetes. Therefore, we sought to determine if insulin receptor-mediated signaling specifically within the RPE plays a role in the development of oxidative stress and inflammatory markers in the retina and the RPE.
Methods :
The insulin receptor (IR) was conditionally inactivated in the RPE by breeding mice expressing a floxed IR with the Best1-cre mouse. Wildtype and conditional knockout mice were made diabetic by injection with streptozotocin and analysis was performed 4 weeks following onset of diabetes. Oxidative stress was measured by dihydroethidium staining of fresh frozen retinal cryosections spanning the optic nerve. Gene Expression of inflammatory and oxidative stress markers were measured by quantitative PCR on dissected retinal and RPE tissue. Markers included ICAM-1, Nos-2, Cox2, TNFα, and IL-1β.
Results :
Loss of RPE-specific insulin receptor-mediated signaling modulated the presence of oxidative stress in the retina of diabetic mice. Moreover, inflammatory molecules were differentially altered in the RPE and retina.
Conclusions :
Insulin receptor-mediated signal transduction is important for maintenance of RPE and retinal health and may be a valid therapeutic target in prevention of the earliest signs of diabetic retinopathy.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.