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Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion

1
Augusta Biomedical Research Corporation, Augusta, GA 30901, USA
2
Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
3
Department of Pharmaceutical Sciences, South University, School of Pharmacy, Savannah, GA 31406, USA
4
Department of Pharmacology and Toxicology, Augusta University, Augusta, GA 30901, USA
5
Department of Pharmacy, Doctors Hospital of Augusta, Augusta, GA 30909, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 3969; https://doi.org/10.3390/ijms20163969
Received: 10 July 2019 / Revised: 5 August 2019 / Accepted: 6 August 2019 / Published: 15 August 2019
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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Abstract

Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases. View Full-Text
Keywords: TXNIP; retinal inflammation; inflammasome; ischemia reperfusion; visual function TXNIP; retinal inflammation; inflammasome; ischemia reperfusion; visual function
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Coucha, M.; Shanab, A.Y.; Sayed, M.; Vazdarjanova, A.; El-Remessy, A.B. Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion. Int. J. Mol. Sci. 2019, 20, 3969.

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