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

  1. Rose A. Gubitosi-Klug1,
  2. Ramaprasad Talahalli1,
  3. Yunpeng Du2,
  4. Jerry L. Nadler3 and
  5. Timothy S. Kern24
  1. 1Department of Pediatrics, Case Western Reserve University/Rainbow Babies and Children's Hospital, Cleveland, Ohio
  2. 2Department of Medicine, Case Western Reserve University, Cleveland, Ohio
  3. 3Department of Internal Medicine, University of Virginia, Charlottesville, Virginia
  4. 4Veterans Administration Medical Center Research Service 151, Cleveland, Ohio
  1. Corresponding author: Rose Gubitosi-Klug, MD, PhD, Division of Pediatric Endocrinology and Metabolism, Case Medical Center, 11100 Euclid Ave., Rainbow Babies and Children's Hospital, Room 737, Cleveland, OH 44106. E-mail: rose.gubitosi-klug{at}case.edu

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 17 March 2008. DOI: 10.2337/db07-1217.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 20, 2008.
    • Received August 29, 2007.
| Table of Contents

This Article

  1. Diabetes vol. 57 no. 5 1387-1393
  1. Figures
  2. All Versions of this Article:
    1. db07-1217v1
    2. db07-1217v2
    3. 57/5/1387 most recent