Inhibition of HIF ‐1 α decreases expression of pro‐inflammatory IL ‐6 and TNF ‐ α in diabetic retinopathy

Purpose Recent studies demonstrate that pro‐inflammatory cytokines ( PIC s, i.e. IL ‐1 β , IL ‐6 and TNF ‐ α ) in retinal tissues are likely involved in the development of diabetic retinopathy ( DR ). In this report, we particularly examined contributions of hypoxia inducible factor subtype 1 α ( HIF ‐1 α ) to the expression of PIC s and their receptors in diabetic retina. Methods Streptozotocin ( STZ ) was systemically injected to induce hyperglycaemia in rats. ELISA and Western blot analysis were employed to determine the levels of HIF ‐1 α and PIC s as well as PIC receptors in retinal tissues of control rats and STZ rats. Results The levels of retinal HIF ‐1 α were significantly increased in STZ rats 4–10 weeks after induction of hyperglycaemia as compared with control animals. With increasing HIF ‐1 α retinal PIC s including IL ‐1 β , IL ‐6 and TNF ‐ α , their respective receptors, namely IL ‐1R, IL ‐6R and TNFR 1, were also elevated in STZ rats. Moreover, inhibition of HIF ‐1 α by injection of 2‐methoxyestradiol (2‐ MET ) significantly decreased the amplified expression IL ‐6, TNF ‐ α , IL ‐6R and TNFR 1 in diabetic retina, but did not modify IL ‐1 β pathway. In addition, we examined protein expression of Caspase‐3 indicating cell apoptosis in the retina of STZ rats after infusing 2‐ MET , demonstrating that 2‐ MET attenuated an increase in Caspase‐3 evoked by STZ . Conclusion Hypoxia inducible factor subtype 1α (HIF‐1α) activated in diabetic retina is likely to play a role in regulating pathophysiological process via IL ‐6 and TNF ‐ α mechanism. This has pharmacological implications to target specific HIF ‐1 α , IL ‐6 and TNF ‐ α signalling pathway for dysfunction and vulnerability related to DR .