Abstract
Existing animal models with rod-dominant retinas have shown that hyperglycemia injures neurons, but it is not yet clearly understood how blue cone photoreceptors and retinal ganglion cells (RGCs) deteriorate in patients because of compromised insulin tolerance. In contrast, northern tree shrews (Tupaia Belangeri), one of the closest living relatives of primates, have a cone-dominant retina with short wave sensitivity (SWS) and long wave sensitivity (LWS) cones. Therefore, we injected animals with a single streptozotocin dose (175 mg/kg i.p.) to investigate whether sustained hyperglycemia models the features of human diabetic retinopathy (DR). We used the photopic electroretinogram (ERG) to measure the amplitudes of A and B waves and the photopic negative responses (PhNR) to evaluate cone and RGC function. Retinal flat mounts were prepared for immunohistochemical analysis to count the numbers of neurons with antibodies against cone opsins and RGC specific BRN3a proteins. The levels of the proteins TRIB3, ISR-1, and p-AKT/p-mTOR were measured with western blot. The results demonstrated that tree shrews manifested sustained hyperglycemia leading to a slight but significant loss of SWS cones (12%) and RGCs (20%) 16 weeks after streptozotocin injection. The loss of BRN3a-positive RGCs was also reflected by a 30% decline in BRN3a protein expression. These were accompanied by reduced ERG amplitudes and PhNRs. Importantly, the diabetic retinas demonstrated increased expression of TRIB3 and level of p-AKT/p-mTOR axis but reduced level of IRS-1 protein. Therefore, a new non-primate model of DR with SWS cone and RGC dysfunction lays the foundation to better understand retinal pathophysiology at the molecular level and opens an avenue for improving the research on the treatment of human eye diseases.
Highlights
Diabetic retinopathy (DR) is on the priority list of eye conditions according to the World Health Organization
We monitored the animals for 16 weeks and found that these animals demonstrated a progressive decline in BW as compared to the control group, starting at 8 weeks after induction of hyperglycemia (p < 0.01; Figure 1A)
Average blood glucose levels (BGL) fluctuated between 300 mg/dl and 350 mg/dl in the diabetic group during the 16 weeks of observation. Both BGL and BW values were consistent with the decline in insulin levels (8fold, p 3-fold, p
Summary
Diabetic retinopathy (DR) is on the priority list of eye conditions according to the World Health Organization. Tree Shrews and Diabetes vasculature dysfunction are two major pathophysiological features of DR [3]. Retinal dysfunction [4–9] caused by reduced cone sensitivity, abnormal activation of the phototransduction cascade [10, 11], selective loss of S cones [12], glial abnormalities, and thinning of the nerve fiber, the retinal ganglion cell (RGC) layer, and the inner plexiform layer in DR patients [13–15] have not received the necessary attention from researchers. Highlighting the importance of further investigation, hyperglycemia-induced retinal neurodegeneration may precede the microvascular dysfunction and contribute to DR pathogenesis [16–19]. The ability to investigate crosstalk between these two pathologic features of DR depends on establishing animal models that accurately represent diabetic retinopathy pathophysiology in the human eye
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