Elevated Expression of Indoleamine 2,3-Dioxygenase (IDO) and Accumulation of Kynurenic Acid in the Pathogenesis of STZ-Induced Diabetic Cataract in Wistar Rats

Abstract

Purpose: Glycated lens proteins are capable of producing reactive oxygen species (ROS), which, in turn, can oxidize tryptophan (Trp) into kynurenines. Indoleamine 2,3-dioxygenase (IDO), which is expressed in many tissues and which is inducible by interferon-γ (IFN-γ), is able to oxidize Trp into kynurenines. These kynurenines can modify lens proteins and, in fact, kynurenine adducts are markedly increased in lenses with age-related nuclear cataract. Therefore, it has been suggested that lenticular IDO is involved in diabetic cataractogenesis. The aim of the present study was to examine the possible role(s) of IDO in streptozotocin (STZ)-induced diabetic cataract in rats. Methods: Diabetic cataract was induced in male Wistar-NIN rats by IP injection of STZ (34 mg/kg body wt). Slit lamp biomicroscopy was used to monitor progression of the resulting hyperglycemia-induced cataract. Treated and control rats were sacrificed at 30 and 60 days, at which times changes in lenticular levels of IDO activity, IDO mRNA, IFN-γ mRNA (IDO inducer), Trp, kynurenic acid (KYNA), oxidative stress markers (malondialdehyde and carbonyls), antioxidant (reduced glutathione), antioxidant enzymes (glutathione peroxidase and superoxide dismutase), and polyol enzymes (aldose reductase and sorbitol dehydrogenase) were determined and compared. Results: Cataract was observed to begin at 30 days after STZ treatment, and mature cataract was observed 60 days after STZ treatment. Lenticular levels of IDO activity, IDO mRNA, IFN-γ mRNA, Trp, and KYNA increased significantly at 30 days and remained elevated through 60 days. Significant increases were also observed in levels of oxidative stress markers, antioxidant enzymes, and polyol enzymes at 30 and 60 days after STZ treatment. However, the level of reduced GSH decreased by ∼ 50% at both points of determination. Conclusions: Production of IDO was induced in STZ-induced diabetic cataractous lenses, possibly by locally produced IFN- γ. IDO-mediated oxidation of Trp may partly explain the increase in lens KYNA and may thus be implicated in cataractogenesis in concert with the non-enzymic oxidation of Trp by glycated lens proteins.

Keywords:

• diabetic cataract
• IDO
• INF-γ
• kynurenic acid
• oxidative stress
• tryptophan metabolism

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