5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy

Abstract

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-lipoxygenase–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-lipoxygenase–deficient mice, but not in 12/15-lipoxygenase–deficient mice. Retinas from diabetic 5-lipoxygenase–deficient mice also had significantly less leukostasis, superoxide production, and nuclear factor-κB (NF-κB) 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- κB expression. Retinas from diabetic wild-type mice were enriched with receptors for the 5-lipoxygenase metabolite leukotriene B₄. Diabetes-induced histological and biochemical alterations were significantly reduced in 5-lipoxygenase–deficient mice, but not 12/15-lipoxygenase–deficient mice. CONCLUSIONS—5-Lipoxygenase represents a novel pathway for therapeutic intervention of diabetic retinopathy.