Abstract
Purpose :
Diabetic retinopathy (DR) is a common neurovascular complication of diabetes. The diabetic milieu detrimentally impairs several components of the retinal neurovascular unit (NVU) during DR progression, including neurons, vascular endothelium, immune and glial cells of the retina. Streptozotocin (STZ)-induced Sprague Dawley (SD) diabetic rats are known to develop key pathological hallmarks seen in human DR. The aim of this study was to longitudinally characterize the functional and retinal NVU complications in this experimental model at 1-,3- and 6-mos post diabetes.
Methods :
Diabetes was chemically induced in male SD rats with a single intraperitoneal injection of STZ (50mg/kg), for comparison with age-matched vehicle-injected non-diabetic controls. Blood pressure, blood glucose, HbA1c, water intake, body weights, electroretinography (ERG) and optical coherence tomography (OCT) were recorded and analyzed at 1-,3- and 6-mos after diabetes induction. Retinal NVU complications were assessed by immunolabelling of cryosections and flatmounts as well as RT-qPCRs and the Evan’s blue dye assay.
Results :
After 1-mo of diabetes, a significant elevation of blood glucose, HbA1c, and water intake were observed. Retinal gene expression of markers for inflammation (Il-1β, Il-6, Ccl2, Ccl5, Tnfα, and Casp3) and Müller glial dysfunction (Gfap and Hmox1) were also upregulated at this timepoint. ERG a- and b-wave amplitudes and OCT retinal thickness were significantly reduced after 3-mos of diabetes, along with the expression of inwardly rectifying K+ channel 4.1 (Kir4.1) and neurotransmitter recycling enzyme glutamine synthetase (GS). Increased vascular permeability, glial activation (GFAP and IBA1), oxidative stress (HMOX1), and pro-inflammatory responses (RAGE and S100B) were also evident at this timepoint. After 6-mos of diabetes, the number of retinal neurons including photoreceptor cones and rods (Cone arrestin), ganglion cells (BRN3A), amacrine cells (GABA), and bipolar cells (PKCα) were significantly reduced. Vascular pathology including the loss of pericytes (NG2) and increased acellular capillaries (Collagen IV) were also apparent at this timepoint.
Conclusions :
STZ-induced diabetic rats develop functional impairment and NVU pathology. Our findings suggests that SD diabetic rat model is suitable for investigating the underlying disease mechanisms and developing therapeutics for DR.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.