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Transactive response DNA binding protein of 43/histone deacetylase 6 axis alleviates H 2 O 2 -induced retinal ganglion cells injury through inhibiting apoptosis and autophagy.
Journal of Cellular Biochemistry 2019 March
Oxidative damage is believed to contribute to the pathogenesis of diabetic retinopathy (DR). The current study aimed to detect the effects of transactive response DNA binding protein of 43 (TDP-43) on cell damage induced by hydrogen peroxide (H2 O2 ) in retinal ganglion cells (RGCs) and to investigate the molecular mechanisms involved in this process. We observed that TDP-43 was highly expressed in RGC-5 cells induced by H2 O2 , and that repression of TDP-43 obviously ameliorated H2 O2 -induced RGC-5 cell injury. In addition, loss of TDP-43 profoundly mitigated H2 O2 -triggered oxidative stress by decreasing the production of intracellular reactive oxygen species and the activity of oxidative stress indicator malondialdehyde, as well as enhancing the content of antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase to restore the antioxidant defense system. Moreover, suppression of TDP-43 obviously obstructed H2 O2 -induced apoptosis. Meanwhile, knockdown of TDP-43 attenuated the expression of the proapoptotic proteins Bax and Cytochrome c, elevated the anti-apoptotic protein Bcl-2, and suppressed the activation of caspase 3 in H2 O2 -induced RGC-5 cells. Moreover, elimination of TDP-43 inhibited H2 O2 -triggered autophagy, which appeared as decreased expression of LC3II/I and Beclin-1, along with p62 degradation. Importantly, silencing of TDP-43 diminished the expression of histone deacetylase 6 (HDAC6), and HDAC6 also abolished the inhibitory effect of TDP-43 inhibition on H2 O2 -induced apoptosis and autophagy. Collectively, our findings demonstrated that depletion of TDP-43 may protect RGC-5 cells against oxidative stress-mediated apoptosis and autophagy by suppressing its target HDAC6. Thus, the TDP-43/HDAC6 axis might be a promising strategy for the treatment of DR.
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