Neural degeneration in the retina of the streptozotocin-induced type 1 diabetes model

Abstract

Diabetic retinopathy, a vision-threatening disease, has been regarded as a vascular disorder. However, impaired oscillatory potentials (OPs) in the electroretinogram (ERG) and visual dysfunction are recorded before severe vascular lesions appear. Here, we review the molecular mechanisms underlying the retinal neural degeneration observed in the streptozotocin-(STZ-) induced type 1 diabetes model. The renin-angiotensin system (RAS) and reactive oxygen species (ROS) both cause OP impairment and reduced levels of synaptophysin, a synaptic vesicle protein for neurotransmitter release, most likely through excessive protein degradation by the ubiquitin-proteasome system. ROS also decrease brain-derived neurotrophic factor (BDNF) and inner retinal neuronal cells. The influence of both RAS and ROS on synaptophysin suggests that RAS-ROS crosstalk occurs in the diabetic retina. Therefore, suppressors of RAS or ROS, such as angiotensin II type 1 receptor blockers or the antioxidant lutein, respectively, are potential candidates for neuroprotective and preventive therapies to improve the visual prognosis.

Figure 1

Expression of angiotensin II type 1 receptor and synaptophysin in the mouse retina. Expression of AT1R (green) in the normal retina (A–C). The boxed area in A is magnified in B and C (merged in C), and the boxed areas in C are magnified in the insets of C. AT1R is coexpressed with synaptophysin (pink), a presynaptic vesicle protein, in the IPL (arrow in the upper inset of C) and OPL (arrows in B and the lower inset of C). AT1R, angiotensin II type 1 receptor; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer [28].

Figure 2

Oxidative stress in the retina of the STZ-induced diabetes model mouse. Dihydroethidium (DHE) indicates ROS in the retina (a). The level of diabetes-induced ROS in the retina is decreased by constant lutein treatment. Fluorescence intensity in the INL relative to that of nondiabetic mice was measured by the Image J program (b). DHE, dihydroethidium; ROS, reactive oxygen species; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer (original copyright; [8], Figure 1, reproduced with the kind permission of Springer Science + Business Media.)

Figure 3

Model of retinal neural degeneration and visual impairment in the STZ-induced diabetes model mouse. Cross-talk between AT1R signaling and ROS is involved in the neural degeneration of the diabetic retina. Downstream of both these effectors, ERK activation reduces synaptophysin, while ROS also decrease BDNF. These changes impair visual function most probably through synaptic network abnormalities and neuronal apoptosis. AT1R, angiotensin II type 1 receptor; ROS, reactive oxygen species; BDNF, brain-derived neurotrophic factor.