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P<P, published online ahead of print October 15, 2009
(Investigative Ophthalmology and Visual Science. )
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3557
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Elevated Glucose Increases Synthesis of Leukotrienes in the Mouse Model of Diabetic Retinopathy

Ramaprasad Talahalli,1 Simona Zarini,2 Nader Sheibani,3 Robert C Murphy,4 and Rose A Gubitosi-Klug5

1Pediatrics, Case Western Reserve University, Cleveland, United States 2Pharmacology, University of Colorado Denver, Denver, United States 3Ophthalmology and Visual Sciences, University of Wisconsin, Madison, United States 4Pharmacology, University of Colorado Denver, Denver, United States 5Pediatrics, Case Western Reserve University, Cleveland, United States

Correspondence: Rose Gubitosi-Klug, Email: rose.gubitosi-klug{at}case.edu

Abstract

Purpose: Evidence suggests that capillary degeneration in early diabetic retinopathy results from chronic inflammation, and leukotrienes have been implicated in this process. This study investigates cellular sources of leukotriene biosynthesis in diabetic retinas, and the effects of hyperglycemia on leukotriene production.

Methods: Retinas and bone marrow cells were collected from diabetic and nondiabetic mice. Mouse retinal glial cells and retinal endothelial cells (mREC) were cultured under non-diabetic and diabetic conditions. Production of leukotriene metabolites was assessed by mass spectrometry, and western blots quantitated expression of enzymes and receptors involved in leukotriene synthesis and signaling.

Results: Bone marrow cells from nondiabetic mice expressed 5-lipoxygenase, the enzyme required for initiation of leukotriene synthesis, and produced leukotriene B4 (LTB4) when stimulated with the calcium ionophore A23187. Notably, LTB4 synthesis was increased three-fold over normal (p<0.03) in bone marrow cells from diabetic mice. In contrast, retinas from nondiabetic or diabetic mice neither produced leukotrienes nor 5-lipoxygenase mRNA. Despite not being able to initiate leukotriene biosynthesis, addition of exogenous leukotriene A4 (LTA4; the precursor of LTB4) to retinas resulted in robust production of LTB4. Retinal glial cells likewise synthesized LTB4 from LTA4, while mREC produced both LTB4 and the cysteinyl leukotrienes. Culturing the retinal cells in high glucose concentrations enhanced leukotriene synthesis and selectively increased expression of the LTB4 receptor, BLT1. Antagonism of the BLT1 receptor inhibited LTB4-induced mREC cell death.

Conclusions: Transcellular delivery of LTA4 from marrow-derived cells to retinal cells results in generation of LTB4 and death of endothelial cells, and thus might contribute to chronic inflammation and retinopathy in diabetes.

Key Words: diabetic retinopathy • glial cell • retinal vasculature • leukotrienes • inflammation






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