Original ContributionNrf2 signaling modulates cigarette smoke-induced complement activation in retinal pigmented epithelial cells
Section snippets
Immunohistochemistry
Human autopsy eyes (n=20) were obtained from the Ocular Pathology Division at the Wilmer Eye Institute after obtaining Institutional Review Board approval. Donors were classified as “unaffected” (n=8) if they had no history of AMD or histopathologic evidence of drusen. Early AMD donors (n=12) had an AMD history, and macular drusen (n=9), but no late-stage disease such as geographic atrophy or choroidal neovascularization. Eyes were fixed in 4% formaldehyde, paraffin embedded, and sectioned at 4
Nrf2 immunolabeling corresponds with AMD histopathology
To demonstrate the relevance of Nrf2 signaling in AMD, we assessed the distribution of Nrf2 immunolabeling in the RPE of unaffected controls from a wide age range (n=8; mean, 56 years; range, 8 months–84 years) and in early AMD (n=12; mean, 80 years, range, 60–96 years; Table 1). In the absence of oxidative stress, Nrf2 is tethered to Kelch-like ECH-associated protein 1 in the cytoplasm and is degraded by the proteasome. With oxidative stress, Nrf2 expression is induced and, importantly, Nrf2
Discussion
Cigarette smoking is a powerful risk factor for AMD, and Nrf2 signaling has been hypothesized to play a protective role against this complex chemical oxidant. Evidence linking impaired Nrf2 signaling with human AMD has been lacking. Our study addresses this deficiency by observing Nrf2 immunolabeling in human maculas that correlated with AMD histopathology. Our work starts to unravel the complex protective effect of Nrf2 signaling in RPE cells against the potential toxicity of a complex
Acknowledgments
We thank Mike Sporn, M.D., Dartmouth School of Medicine, for providing CDDO-Im. This work was supported by EY14005 (J.T.H.), EY019904 (J.T.H.), P50HL107169 (S.B.), R01CA140492 (S.B.), a Thome Foundation Award in AMD (J.T.H.), a Research to Prevent Blindness Senior Scientist Award (J.T.H.), a Wilmer Core Grant, EY001765, an unrestricted grant from Research to Prevent Blindness, and gifts from the Merlau family and Aleda Wright. J.T.H. is a Robert Bond Welch Professor.
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2022, Journal of EthnopharmacologyCitation Excerpt :More important, Nrf2 activation may be the major mechanism of esculetin because Nrf2 is one of core elements in the anti-oxidation and anti-inflammation. And Wang et al. reported that Nrf2 activation could reduce the C3 expression in the retinal pigmented epithelial cells induced by cigarette smoke extract or IL1β (Wang et al., 2014), which was consistent with the present research. Therefore, reducing the renal tubular C3 expression may be the downstream effect of Nrf2 activation by esculetin.
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These authors contributed equally to this work.