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P. L. Singh, T. S. Devi, K.-I. Hosoya, T. Terasaki, A. Shalve, R. A. Kowluru, L. Perrone; Hexosamine Induction of Thioredoxin-Interacting Protein Expression Mediates Oxidative Stress and Inflammatory Response in Retinal Endothelial Cells: Implications of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4919.
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Chronic hyperglycemia and the associated oxidative stress play a major role in the development of diabetic retinopathy. We examined whether the hexosamine biosynthesis pathway (HBP) mediates high glucose (HG)-induced thioredoxin-interacting protein (TXNIP) expression, an endogenous inhibitor of thioredoxin, and causes reactive oxygen species (ROS) generation and inflammatory gene expression in retinal endothelial cells in culture.
Diabetes was induced in rats by streptozotocin for 8 weeks and the HBP flux and TXNIP expression were determined in the retina by Western blotting. Induction of TXNIP by HG and HBP was measured by Quantitative reverse transcription PCR (Q-RTPCR) in retinal endothelial cells (EC). Transcription factors and co-factors associated with the TXNIP promoter in response to HBP flux were identified by Chromatin Immunoprecipitation (ChIP). To evaluate the downstream effects of TXNIP on endothelial cell function: (i) we over expressed human TXNIP in retinal endothelial cells; and (ii) knocked down TXNIP expression by RNA interference.
HBP flux, TXNIP and Fibronectin (FN) are increased in the retina of diabetic rats. Treatment of EC cells with HG or GlcN increases TXNIP expression and the recruitment of USF1, USF2, and p300 on TXNIP promoter. TXNIP over expression in EC leads to ROS accumulation and FN and cyclooxygenase (Cox) 2 mRNA expression while TXNIP silencing reverses these changes.
Elevated HBP flux under hyperglycemia causes TXNIP expression leading to cellular oxidative stress, ECM expression and inflammation that are considered to be causative factors for the development of diabetic retinopathy.
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