5-lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy

OBJECTIVE-Lipoxygenases are regulators of chronic inflamation and oxidative stress generation. We evaluated the role of 5-and 12-lipoxygenases in the development of diabetic retinopathy. RESEARCH DESIGN AND METHODS-Wild-type mice, 5-li-poxygenase- deficient mice, and 12/15-lipoxygenase- deficient mice were assessed 1) after 9 months of diabetes for retinal histopathology and leukotriene receptor expression and 2) after 3 months of diabetes for leukostasis and retinal superoxide generation. RESULTS-Diabetic wild-type mice developed the expected degeneration of retinal capillaries and pericytes and increases in both leukostasis and superoxide production (P < 0.006). We found no evidence of diabetes-induced degeneration of retinal ganglion cells in these animals. The vascular histopathology was significantly inhibited in 5-li-poxygenase- deficient mice, but not in 12/15-lipoxygenase- deficient mice. Retinas from diabetic 5-li-poxygenase- deficient mice also had significantly less leukostasis, superoxide production, and nuclear factor-kappa B (NF-kappa B) expression (all P < 0.006), whereas retinas from diabetic 12/15-lipoxygenase- deficient mice had significantly less leukostasis (P < 0.005) but not superoxide production or NF-kappa B expression. Retinas from diabetic wild-type mice were enriched with receptors for the 5-lipoxygenase metabolite leukotriene B-4. Diabetes-induced histological and biochemical alterations were significantly reduced in 5-li-poxygenase- deficient mice, but not 12/15-lipoxygenase- deficient mice. CONCLUSIONS-5-Lipoxygenase represents a novel pathway for therapeutic intervention of diabetic retinopathy.