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Takeshi Yoshida, Shikun He, Christine Spee, Stephen J. Ryan, Jr., David R. Hinton; The Role Of Sirt1 In The Pathogenesis Of Dry Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3193.
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Sirtuin1 (sirt1) is a NAD+-dependent deacetylase that modifies many of the pleiotropic pathways associated with oxidative metabolism. The aim of the present study is to investigate the role of sirt1 in the pathogenesis of dry age-related macular degeneration (AMD).
Cryostat retinal sections from dry AMD patients and controls were used to analyze the expression of sirt1. Early passage cultured human fetal RPE cells were used for in vitro experiments. Sirt1 gene expression was knocked down using specific siRNA, and then the RPE cells were then exposed to tert-butylhydroquinone (tBH; 0-100uM) for 16 hours. Acetylated-p53, cleaved-caspase3 protein and NF-E2-related factor 2 (nrf2) protein nuclear translocation in the RPE cells were quantified by Western blotting after the treatment of sirt1 siRNA and tBH. Furthermore, apoptosis induced by knocking down of sirt1 and tBH exposure was quantified by TUNEL assay.
The expression of sirt1 in RPE of dry AMD patients was lower than in age-matched control eyes. In vitro, after sirt1 knock down by siRNA, the oxidative stress-induced acetylated-p53 and cleaved-caspase3 expression were significantly increased in fetal RPE cells. Inhibition of sirt1 expression by siRNA also reduced oxidative stress-induced nrf2 nuclear translocation in the RPE cells. Furthermore, apoptosis in fetal RPE cells following knockdown of sirt1 by siRNA was markedly increased after the oxidative stress.
Our data show that sirt1 plays an important role in anti-oxidative stress and in pathogenesis of dry AMD. These results suggest that sirt1 might be a therapeutic approach for the treatment of dry AMD.
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