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. 2016 Nov 18;9(11):1591-1597.
doi: 10.18240/ijo.2016.11.09. eCollection 2016.

Upregulated inflammatory associated factors and blood-retinal barrier changes in the retina of type 2 diabetes mellitus model

Rui-Jin Ran  1 , Xiao-Ying Zheng  2 , Li-Ping Du  2 , Xue-Dong Zhang  2 , Xiao-Li Chen  2 , Shen-Yin Zhu  2
Affiliations

Upregulated inflammatory associated factors and blood-retinal barrier changes in the retina of type 2 diabetes mellitus model

Rui-Jin Ran et al. Int J Ophthalmol. .

Abstract

Aim: To examine the expression of high mobility group box-1 (HMGB-1) and intercellular adhesion molecule-1 (ICAM-1) in the retina and the hippocampal tissues; and further to evaluate the association of these two molecules with the alterations of blood-retinal barrier (BRB) and blood-brain barrier (BBB) in a rat model of type 2 diabetes.

Methods: The type-2 diabetes mellitus (DM) model was established with a high-fat and high-glucose diet combined with streptozotocin (STZ). Sixteen weeks after DM induction, morphological changes of retina and hippocampus were observed with hematoxylin-eosin staining, and alternations of BRB and BBB permeability were measured using Evans blue method. Levels of HMGB-1 and ICAM-1 in retina and hippocampus were detected by Western blot. Serum HMGB-1 levels were determined by enzyme-linked immunosorbent assay (ELISA).

Results: A significantly higher serum fasting blood glucose level in DM rats was observed 2wk after STZ injection (P<0.01). The serum levels of fasting insulin, Insulin resistance homeostatic model assessment (IRHOMA), total cholesterol (TC), total triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) in the DM rats significantly higher than those in the controls (all P<0.01). HMGB-1 (0.96±0.03, P<0.01) and ICAM-1 (0.76±0.12, P<0.05) levels in the retina in the DM rats were significantly higher than those in the controls. HMGB-1 (0.83±0.13, P<0.01) and ICAM-1 (1.15±0.08, P<0.01) levels in the hippocampal tissues in the DM rats were also significantly higher than those in the controls. Sixteen weeks after induction of DM, the BRB permeability to albumin-bound Evans blue dye in the DM rats was significantly higher than that in the controls (P<0.01). However, there was no difference of BBB permeability between the DM rats and controls. When compared to the controls, hematoxylin and eosin staining showed obvious irregularities in the DM rats.

Conclusion: BRB permeability increases significantly in rats with type-2 DM, which may be associated with the up-regulated retinal expression of HMGB-1 and ICAM-1.

Keywords: blood-brain barrier; blood-retinal barrier; diabetes mellitus; high mobility group box-1 protein; permeability; rats.

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Figures

Figure 1
Figure 1. BW of rats with type 2 DM and normal controls
BW (g) was measured at weekly intervals starting at 2wk prior to STZ/vehicle injection to the end of the study period. Data are mean±SD (n=8 per group). STZ: Streptozotocin; DM: Diabetes mellitus. aP<0.05 vs normal control; bP<0.01 vs normal control.
Figure 2
Figure 2. Representative images of hippocampal and retinal tissues with HE staining
A: The CA1 region of rat hippocampus used for study; B: Hippocampal tissue in the normal control group: no obvious histopathological abnormalities were found; C: Hippocampal tissue in the type 2 DM group: the pyramidal cells appeared decreased in quantity and were arranged irregularly; D: Retinal tissue in the normal control group: the shape of retinal cells in each layer was normal and these cells were lined up orderly; E: Retinal tissue in the type 2 DM group: the edema of retinal GCL, thickening of inner plexiform layer and disordered arrangement of INL. Original magnification was 400× except that the magnification in A was 100×. GCL: Ganglion cell layer; INL: Iinner nuclear layer; ONL: Outer nuclear layer; RPE: Retinal pigment epithelium layer.
Figure 3
Figure 3. Permeability of BRB and BBB in the normal control and type 2 DM rats
A: BRB permeability, data are presented as µL plasma ×g retinal wet weight−1 hour−1 and represent the mean±SD of 6-8 rats. bP<0.01 vs normal control; B: BBB permeability, data are presented as µg of EB per wet weight (mg) of hippocampus and represent the mean±SD of 8 rats. The permeability of BRB and BBB was estimated by quantification of extravasated EB as described in Methods. No significant difference was found between the normal control and type 2 DM group.
Figure 4
Figure 4. Protein expression of HMGB-1 and ICAM-1 in rat retina and hippocampus
A: Representative Western blot showing the protein expression of HMGB-1 and ICAM-1 in rat retina and hippocampus. Equal amounts of proteins were loaded and Actin-beta was used as a loading control, n=4 experiments; B: Column diagrams and bars representing the ratio of the scanned immunoblots of HMGB-1 and ICAM-1 to that of Actin-beta. Data are shown as mean±SD, n=4 experiments, aP<0.05 vs normal control, bP<0.01 vs normal control.
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