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 inflammation and oxidative stress generation. We evaluated the role of 5- and 12-lipoxygenases in the development of diabetic retinopathy.


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-kappaB (NF-kappaB) 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- kappaB 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-lipoxygenase-deficient mice, but not 12/15-lipoxygenase-deficient mice.


CONCLUSIONS
5-Lipoxygenase represents a novel pathway for therapeutic intervention of diabetic retinopathy.
Gubitosi-Klug
Rose A
RA
Department of Pediatrics, Case Western Reserve University/Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106, USA. rose.gubitosi-klug@case.edu
Talahalli
Ramaprasad
R
Du
Yunpeng
Y
Nadler
Jerry L
JL
Kern
Timothy S
TS
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002196:Capillaries / Q000473:pathology; D003930:Diabetic Retinopathy / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000201:enzymology / Q000473:pathology; D012162:Retinal Degeneration / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000201:enzymology; D012171:Retinal Vessels / Q000473:pathology
C475064:12-15-lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase