Hydrogen Sulfide: A Potential Therapeutic Target in the Development of Diabetic Retinopathy

PURPOSE: Hyperglycemia damages the retinal mitochondria, and the mitochondrial damage plays a central role in the development of diabetic retinopathy. Patients with diabetes also have higher homocysteine levels, and abnormalities in homocysteine metabolism result in decreased levels of hydrogen sulfide (H(2)S), an endogenous gasotransmitter signaling molecule with antioxidant properties. This study aimed to investigate the role of H(2)S in the development of diabetic retinopathy. METHODS: Streptozotocin-induced diabetic mice were administered a slow releasing H(2)S donor GYY4137 for 6 months. The retina was used to measure H(2)S levels, and their retinal vasculature was analyzed for the histopathology characteristic of diabetic retinopathy and oxidative stress, mitochondrial damaging matrix metalloproteinase-9 (MMP-9), and mitochondrial integrity. These parameters were also measured in the isolated retinal endothelial cells incubated in high glucose medium containing GYY4137. RESULTS: Administration of GYY4137 to diabetic mice ameliorated decrease in H(2)S and prevented the development of histopathology, characteristic of diabetic retinopathy. Diabetes-induced increase in oxidative stress, MMP-9 activation, and mitochondrial damage were also attenuated in mice receiving GYY4137. Results from isolated retinal endothelial cells confirmed the results obtained from diabetic mice. CONCLUSIONS: Thus, supplementation of H(2)S donor prevents the development of diabetic retinopathy by ameliorating increase in oxidative stress and preserving the mitochondrial integrity. H(2)S donors may provide a novel therapeutic strategy to inhibit the development of diabetic retinopathy.