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Jaya P Gnana-Prakasam, Ashok Mandala; Iron Regulates Canonical Wnt/β-catenin Signaling in Retina. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5980.
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We recently reported iron accumulation in the mouse and human diabetic retinas. Age related macular degeneration (AMD) is also associated with increased iron deposition in the retina. Upregulation of Wnt/β-catenin signaling is found to play a pathogenic role in both diabetic retinopathy and AMD. However, the potential link between iron and Wnt/β-catenin signaling remains unclear. We hypothesize that iron upregulates Wnt/β-catenin signaling via redox regulatory protein p66 Src collagen homologue (Shc)-mediated oxidative stress.
Human RPE cell line ARPE19 was treated with Ferric ammonium citrate (FAC) (n=6) to induce iron accumulation and Wnt/β-catenin signaling was assessed. Wnt/β-catenin pathway (TCF/LEF) reporter kit was used to monitor the activity of Wnt/β-catenin. Expression levels of β-catenin signaling components were analyzed in-vivo using mice treated with iron-dextran intraperitoneally (n=7) for 8 weeks. ARPE19 cells along with iron were treated with anti-oxidant N-acetyl cysteine (NAC), iron chelator deferiprone or Peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate and checked for Wnt/β-catenin signaling. Two-tailed Student's t-test was used for statistical analysis.
ARPE19 cells treated with iron had increase in phosphorylated lipoprotein-related protein-6 (LRP6) and glycogen synthase kinase-3β (GSK-3β), and in β-catenin expression levels by western blot. ARPE19 cells treated with iron had increase in luciferase activity when transfected with TCF/LEF luciferase vector, a Wnt pathway-responsive reporter. β-catenin target genes Axin2 and c-myc were upregulated in iron treated cells. Similarly, mice injected with iron dextran showed increase in retinal β-catenin activation. Treatment of ARPE19 cells with NAC, deferiprone or fenofibrate along with iron prevented the upregulation of Wnt/β-catenin signaling. P66Shc stress adaptor protein, which is known to increase β-catenin activation, was upregulated in iron treated cells. On the contrary, P66Shc levels were downregulated when iron was present along with NAC, deferiprone or fenofibrate.
Iron accumulation increases retinal Wnt/β-catenin signaling through p66Shc induced oxidative stress. This upregulation of β-catenin signaling is reversed by the presence of antioxidant, iron chelator or PPAR alpha agonist indicating a novel role for iron in inducing Wnt/β-catenin pathway during retinal degenerative diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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