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Yan Chen, Zhen-Yang Zhao, Paul Sternberg, Jr., Jiyang Cai; Regulation of Autophagy by Nrf2 in Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2311.
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Autophagy is a lysosome-dependent degradation pathway and is critical for turnover of obsolete organelles and long-lived proteins. It is of particular importance for the function of retinal pigment epithelium (RPE) cells, which are post-mitotic and active in phagocytosis of photoreceptor outer segments. Our recent studies identified aberrant autophagy in the RPE of knockout mice deficient of NF-E2-related factor 2 (Nrf2). The purposes of this study are to further explore Nrf2-mediated regulation of autophagy in the RPE and to better understand the roles of autophagy in the pathogenesis of AMD.
Accumulation of autophogosome and lipofuscin in the RPE of Nrf2 knockout mice at advanced age was monitored by electron microscopy. Nrf2 in cultured primary human RPE cells was down-regulated by RNAi. The level of p62, a downstream target of Nrf2 and a cargo receptor functioning in the autophagic pathway, was evaluated by real-time qPCR and western blot analyses. Basal and starvation-induced autophagy were compared between wild type and Nrf2-deficient RPE cells by monitoring the expression of LC3B-II as well as its subcellular distribution.
Knock down of Nrf2 by siRNA in cultured human RPE cells resulted in decreased p62 mRNA and protein, and reduced basal autophagic flux. Poly-ubiquitinated proteins accumulated in RPE cells when either Nrf2 or p62 was knocked down. Autophagosome, lipofuscin and undigested outer segments were found in the RPE of aged Nrf2 knockout mice.
Nrf2 regulated autophagy in the RPE. In addition to p62, Nrf2 may have other downstream effector proteins in the signaling pathway of autophagy. Abnormal autophagy may contribute to age-related RPE degeneration and AMD.
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