Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury
| Autor: | El-Azab, M F, Baldowski, B R B, Mysona, B A, Shanab, A Y, Mohamed, I N, Abdelsaid, M A, Matragoon, S, Bollinger, K E, Saul, A, El-Remessy, A B |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male N-Methylaspartate Thioredoxin-Disulfide Reductase Ependymoglial Cells Interleukin-1beta Apoptosis Retina Mice Thioredoxins Animals Humans Cells Cultured Aged Inflammation Mice Knockout Tumor Necrosis Factor-alpha Middle Aged Vascular System Injuries Research Papers Mice Inbred C57BL Tyrosine Female Neurotoxicity Syndromes Carrier Proteins Glaucoma Open-Angle |
| Popis: | Retinal neurodegeneration is an early and critical event in several diseases associated with blindness. Clinically, therapies that target neurodegeneration fail. We aimed to elucidate the multiple roles by which thioredoxin-interacting protein (TXNIP) contributes to initial and sustained retinal neurodegeneration.Neurotoxicity was induced by intravitreal injection of NMDA into wild-type (WT) and TXNIP-knockout (TKO) mice. The expression of apoptotic and inflammatory markers was assessed by immunohistochemistry, elisa and Western blot. Microvascular degeneration was assessed by periodic acid-Schiff and haematoxylin staining and retinal function by electroretinogram.NMDA induced early (1 day) and significant retinal PARP activation, a threefold increase in TUNEL-positive nuclei and 40% neuronal loss in ganglion cell layer (GCL); and vascular permeability in WT but not TKO mice. NMDA induced glial activation, expression of TNF-α and IL-1β that co-localized with Müller cells in WT but not TKO mice. In parallel, NMDA triggered the expression of NOD-like receptor protein (NLRP3), activation of caspase-1, and release of IL-1β and TNF-α in primary WT but not TKO Müller cultures. After 14 days, NMDA induced 1.9-fold microvascular degeneration, 60% neuronal loss in GCL and increased TUNEL-labelled cells in the GCL and inner nuclear layer in WT but not TKO mice. Electroretinogram analysis showed more significant reductions in b-wave amplitudes in WT than in TKO mice.Targeting TXNIP expression prevented early retinal ganglion cell death, glial activation, retinal inflammation and secondary neuro/microvascular degeneration and preserved retinal function. TXNIP is a promising new therapeutic target for retinal neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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