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Jorgelina Muriel Calandria, Aram Asatryan, John Cefalu, Nicolas G Bazan; HMGB1 potentiates NPD1-mediated protection to oxidative stress through the inhibition of PTPRZ1-mediated activation of the β-catenin pathway. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4248.
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© ARVO (1962-2015); The Authors (2016-present)
High Mobility Group Box-1 (HMGB1) is an ubiquitous binding protein involved in nuclear and mitochondrial homeostasis as well as in extracellular signaling. The latter is currently associated with chemotaxis and cell activation leading to an enhanced immune response (Oppenheim J and Yang D, Curr Opin Immunol. 2005). We have identified HMGB1 as a key of a gene network engaged in neuroprotectin D1 (NPD1) gene modulation during oxidative stress in RPE cells. Moreover, the PTN (previously identified Pleiotrophin) receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1) seems to be linked to the response. Thus, we hypothesized that HMGB1 mediates RPE survival signaling elicited by NPD1.
To assess the role of HMGB1, ARPE-19 and human primary RPE cells were incubated with HMGB1 during oxidative stress in the presence or absence of NPD1. To compare the extracellular properties of HMGB1, the protein was also overexpressed. Apoptosis was measured using Hoechst staining. To determine if extracellular HMGB1 was affecting PTPRZ1, the receptor tyrosine phosphatase was silenced and the effects of HMGB1 on the mobilization of β-catenin were assessed by immunocytochemistry and TCF/LEF reporter activity.
Over-expression of HMGB1 have a protective effect against oxidative stress mediated RPE cell damage. Also exogenously-added HMGB1 displayed remarkable protective properties, preventing RPE cell apoptosis triggered by oxidative stress. PTPRZ1 knockdown resulted in an increase in β-catenin mobilization from the plasma membrane to the cytoplasm mimicking the effects of HMGB1 and suggesting an inhibition of PTPRZ1.
Extracellular HMGB1 bioactivity on RPE cells showed protective bioactivity against oxidative stress and β-catenin involvement, providing a link with NPD1-mediated wnt signaling. Since RPE cells integrity is critical to sustain photoreceptor cells function, converging NPD1 -mediated signaling pathways counteract uncompensated oxidative stress events at the initiation and early progression of retinal degenerations.
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