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Oxidative stress-mediated TXNIP loss causes RPE dysfunction
- Source :
- Experimental and Molecular Medicine, Vol 51, Iss 10, Pp 1-13 (2019), Experimental & Molecular Medicine
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
Abstract
- The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood–retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.<br />Macular degeneration: crucial protein identified A protein found in retinal cells promotes the development of age-related macular degeneration and may provide a therapeutic target. Sight loss through macular degeneration is triggered by disruption to the retinal pigment epithelium (RPE), a layer of cells that carries nutrients to the eye. RPE cells can be disrupted under oxidative stress conditions, but how this influences macular degeneration is unclear. Jeong-Ki Min and Sang-Hyun Lee at the Korea Research Institute of Bioscience and Biotechnology in Daejeon, South Korea, and co-workers found that oxidative stress reduces levels of the thioredoxin-interacting protein (TXNIP) in human RPE cell cultures. This interrupts cellular communication and disturbs the balance between cell proliferation and cell recycling. It also increases the levels of proteins that promote excess blood vessel formation, a key process contributing to macular degeneration.
- Subjects :
- Vascular Endothelial Growth Factor A
0301 basic medicine
genetic structures
Angiogenesis
Clinical Biochemistry
lcsh:Medicine
Retinal Pigment Epithelium
medicine.disease_cause
Biochemistry
Macular Degeneration
Thioredoxins
0302 clinical medicine
Cell Movement
Blood-Retinal Barrier
lcsh:QD415-436
Phosphorylation
chemistry.chemical_classification
Cell biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Molecular Medicine
TXNIP
Retina
Article
Tight Junctions
lcsh:Biochemistry
Stress signalling
03 medical and health sciences
Downregulation and upregulation
Macroautophagy
Autophagy
medicine
Animals
Humans
Molecular Biology
Reactive oxygen species
Retinal pigment epithelium
Cell growth
lcsh:R
Hypoxia-Inducible Factor 1, alpha Subunit
eye diseases
Oxidative Stress
030104 developmental biology
Gene Expression Regulation
chemistry
sense organs
Tumor Suppressor Protein p53
Carrier Proteins
Reactive Oxygen Species
Oxidative stress
Subjects
Details
- Language :
- English
- ISSN :
- 20926413 and 12263613
- Volume :
- 51
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Experimental and Molecular Medicine
- Accession number :
- edsair.doi.dedup.....bb7fa88d391eaffa769878aa12f84bf6
- Full Text :
- https://doi.org/10.1038/s12276-019-0327-y