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Hint1 mitigates high glucose- and radiation-induced apoptosis and inflammation in human retinal pigment epithelial cells through inhibiting the NF-κB pathway
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W. Luo   , R. Xu , P. Wu , M. Yu , W. Dong |
| Department of Ophthalmology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu Province, China , wupch@lzu.edu.cn |
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Abstract: (10 Views) |
Background: Histidine triad nucleotide-binding protein 1 (Hint1) has been associated with inflammation, apoptosis, and the DNA damage response. However, its potential role in RPE injury induced by high glucose and/or radiation is unclear. We evaluated the protective effects of Hint1 against high-glucose and irradiation-induced RPE cell injury and the underlying mechanism involved the NF-κB pathway. Materials and Methods: The expression of Hint1 was determined in retinas from mice with type 1 diabetes and in human RPE cells with high-glucose and/or irradiation injury. Modulation of Hint1 protein levels was achieved through Hint1-overexpression and knockdown. Cellular apoptosis, DNA damage, cytokine production, and NF-κB activity were measured by flow cytometry, γH2AX immunofluorescence/Western blot, real-time PCR, ELISA, Western blot, and p65 translocation assay. BAY 11-7082 was used for mechanism validation. Result: Expression of Hint1 was down-regulated in diabetic retinal tissues and in ARPE-19 cells under combined exposure to hyperglycemia and radiation conditions with the most severe downregulation seen in the case of combined stimuli. The combination increased apoptosis, γ-H2AX levels, TNF-α, IL-6, and IL-8 expression, and nuclear translocation of phosphorylated p65. Overexpression of Hint1 reduced apoptosis, DNA damage, and cytokine release, whereas knockdown of Hint1 increased them. Inhibition of NF-κB partially reversed the detrimental effects of Hint1 deficiency. Conclusion: Hint1 attenuates high-glucose- and radiation-induced RPE cell injury, particularly under combined stress, at least in part by suppressing NF-κB activation. These findings suggest that the Hint1/NF-κB axis may represent a potential therapeutic target for retinal injury associated with diabetes and radiotherapy. |
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| Keywords: Histidine triad nucleotide-binding protein 1, diabetic retinopathy, retinal pigment epithelium, radiation injuries, apoptosis |
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Full-Text [PDF 1377 kb]
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Type of Study: Original Research |
Subject:
Radiation Biology
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