Abstract
Purpose:
To test the hypothesis that brain-derived neurotrophic factor (BDNF)-mediated neuroprotection is reduced by high-mobility group box-1 (HMGB1) in the diabetic retina.
Methods:
Paired vitreous and serum samples from 46 PDR and 34 nondiabetic patients were assayed for BDNF, HMGB1, soluble receptor for advanced glycation end products (sRAGE), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1) and thiobarbituric acid reactive substances (TBARS). In addition, we examined retinas of diabetic and HMGB1 intravitreally injected rats for the expression of BDNF, HMGB1, synaptophysin, TBARS and cleaved caspase-3. Retinas were dissected out, snap frozen and stored at -700C until analysis was done. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) were used.
Results:
BDNF was not detected in vitreous samples. BDNF levels were significantly lower in serum samples from patients with PDR compared with nondiabetic patients (p=0.015), whereas HMGB1, sRAGE, sICAM-1 and TBARS levels were significantly higher in PDR serum samples (p<0.001; p=0.008; p=0.019; p=0.011, respectively). MCP-1 levels did not differ significantly between patients with PDR and nondiabetic patients (p=0.836). There was a significant inverse correlation between serum levels of BDNF and HMGB1 (r=0.342; p=0.049). Diabetes and intravitreal administration of HMGB1 induced significant upregulation of the expression of HMGB1, TBARS and cleaved caspase-3, whereas the expression of BDNF and synaptophysin was significantly downregulated in rat retinas.
Conclusions:
Our data suggest that diabetes-induced increased oxidative stress, down-regulation of BDNF and synaptophysin and upregulation of cleaved caspase-3 were also induced by HMGB1. Collectively, our present data suggest that blocking HMGB1 signaling pathways might be a novel therapeutic strategy for neuronal dysfunction in vision-threatening diabetic retinopathy.
Keywords: 499 diabetic retinopathy •
695 retinal degenerations: cell biology