Increase in retinal hypoxia-inducible factor-2α, but not hypoxia, early in the progression of diabetes in the rat.

Hypoxia and the associated hypoxia-inducible factors (HIFs) may be influential in the progression of diabetic retinopathy. However, little is known of the extent of hypoxia and the levels of HIFs early in the progression of the disease. In the current study, we injected the oxygen-dependent probe pimonidazole (Hypoxyprobe™-1) into diabetic rats, and also performed immunohistochemistry to determine the retinal levels of HIF-1α and HIF-2α. The rats were made diabetic using a single injection of streptozotocin (STZ; 60 mg/kg), with vehicle-injected rats used as non-diabetic controls. The measurements of hypoxia and HIF levels were obtained three weeks following STZ injection, at which time we have previously found significant decreases in retinal blood flow in the same model. In the current experiments, no increases in either HIF-1α or hypoxia were observed in the diabetic rats (compared with controls), and there was even a tendency for hypoxia levels to be decreased (tissue more highly oxygenated). However, we did observe an increase in HIF-2α in the retinas of the diabetic rats. Therefore, we conclude that early diabetes-induced increases in HIF-2α occur independently of hypoxia.