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 inflammation 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-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.

• Authors: Rose A Gubitosi-Klug, Ramaprasad Talahalli, Yunpeng Du, Jerry L Nadler, Timothy S Kern
• Journal: Diabetes (Diabetes) Vol. 57 Issue 5 Pg. 1387-93 (May 2008) ISSN: 1939-327X [Electronic] United States
• PMID: 18346986 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 12-15-lipoxygenase
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Arachidonate 5-Lipoxygenase

Topics

• Animals
• Arachidonate 12-Lipoxygenase (deficiency, genetics, metabolism)
• Arachidonate 15-Lipoxygenase (deficiency, genetics, metabolism)
• Arachidonate 5-Lipoxygenase (deficiency, genetics, metabolism)
• Capillaries (pathology)
• Diabetic Retinopathy (complications, enzymology, pathology)
• Disease Models, Animal
• Hyperglycemia (metabolism)
• Mice
• Mice, Knockout
• Retina (enzymology, pathology)
• Retinal Degeneration (enzymology, etiology, pathology)
• Retinal Ganglion Cells (enzymology)
• Retinal Vessels (pathology)