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.
Highlights
Retinal neurodegeneration is an early and common characteristic of several blinding diseases, including diabetic retinopathy, retinopathy of prematurity, traumatic optic neuropathy and glaucoma [1]
Exposure to ocular ischemia reperfusion (IR) injury triggered a significant increase in oxidative stress, evident by increased retinal lipid peroxide 4-hydroxyneonal (4-HNE) expression when compared to sham controls after 1 day of IR injury (Figure 1a)
The increase in thioredoxin interacting protein (TXNIP) mRNA expression remained significantly higher (2–3 fold) at 3 and 14 days post-IR injury when compared to sham controls (Figure 1c)
Summary
Retinal neurodegeneration is an early and common characteristic of several blinding diseases, including diabetic retinopathy, retinopathy of prematurity, traumatic optic neuropathy and glaucoma [1]. Despite the significant progress to develop therapeutics for the treatment of the proliferative stage of ischemic retinopathy, the underlying cause of ischemia/hypoxia remain unresolved, resulting in progression of the disease [2]. We and others have shown that miR-17-5p is a regulator of TXNIP expression in pancreatic cells [9], Müller cells [10] and neural stem cells [11]. Among UPR pathways, IRE1α, an ER bifunctional kinase/RNase has been shown to destabilize the number of RNA and microRNA, including miR-17-5p in pancreatic beta cells [9] and Müller cells [10]. Whether ocular ischemia can induce ER-stress and dysregulate miR-17-5p to sustain TXNIP expression remains unknown
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