Abstract
Thioredoxin Interacting Protein (TXNIP) mediates retinal inflammation, gliosis, and apoptosis in experimental diabetes. Here, we investigate the temporal response of Muller glia to high glucose (HG) and TXNIP expression using a rat Muller cell line (rMC1) in culture. We examined if HG-induced TXNIP expression evokes host defense mechanisms in rMC1 in response to metabolic abnormalities. HG causes sustained up-regulation of TXNIP (2 h to 5 days), ROS generation, ATP depletion, ER stress, and inflammation. Various cellular defense mechanisms are activated by HG: (i) NLRP3 inflammasome, (ii) ER stress response (sXBP1), (iii) hypoxic-like HIF-1α induction, (iv) autophagy/mitophagy, and (v) apoptosis. We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats. Knock down of TXNIP by intravitreal siRNA reduces inflammation (IL-1β) and gliosis (GFAP) in the diabetic retina. TXNIP ablation in vitro prevents ROS generation, restores ATP level and autophagic LC3B induction in rMC1. Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis. TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy.
Highlights
Diabetic retinopathy (DR) is the most common cause of blindness among the working age group people in the US and around the world
We have recently shown that Thioredoxin Interacting Protein (TXNIP) expression is increased in the retina of STZ-induced diabetic rats at both 4 and 8 weeks of diabetes duration [8, 9] and mediates inflammation, gliosis/fibrosis, and apoptosis of retinal cells
We further support our previous findings by showing that the expressions of TXNIP, pro-inflammatory IL-1β, iNOS, and pattern recognition receptors TLR4 and P2X7R in the retina are elevated at 4 weeks of diabetes (Figure 1(a))
Summary
Diabetic retinopathy (DR) is the most common cause of blindness among the working age group people in the US and around the world. DR has long been considered as a microvascular disease associated with vessel basement membrane thickening, blood retinal barrier breakdown, capillary cell death, acellular capillary, neovascularization, and retinal detachment [1]. Recent studies have demonstrated that DR is a neurovascular disease that affects both the blood vessel and neuroglia [2, 3]. Chronic hyperglycemiaassociated oxidative stress and low-grade inflammation are considered to play critical roles in disease initiation and progression of diabetic complications including DR [4,5,6]. We demonstrated that thioredoxin interacting/inhibiting protein (TXNIP) is significantly increased both in the diabetic rat retina in vivo and in vitro in retinal endothelial cells in culture and causes pro-inflammatory gene expression for Cox-2, VEGF-A, ICAM1, RAGE, and sclerotic fibronectin (FN) [8,9,10].
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