Abstract
Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin–angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/β-catenin signaling. Interestingly, aberrant activation of Wnt/β-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/β-catenin signaling and its downstream target genes including renin–angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/β-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/β-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.
Highlights
Iron plays a vital role in the retina with many iron containing proteins involved in the phototransduction cascade[1]
To investigate whether retinal iron accumulation during aging and degenerative diseases modulates canonical Wingless-related integration site (Wnt)/β-catenin signaling, a human retinal pigment epithelial (RPE) cell line ARPE19 was treated with different concentrations of ferric ammonium citrate (FAC) for 24 h
FAC treatment increased the nuclear translocation of β-catenin as the active β-catenin levels in the nuclear fraction increased with FAC treatment but there was no change in the expression levels in the cytosolic fraction (Fig. 1c). mRNA expression of β-catenin downstream target genes Axin[2], cMYC, CCND, and VEGF were significantly upregulated in FAC-treated human RPE cells in a dose dependent manner (Fig. 1d)
Summary
Iron plays a vital role in the retina with many iron containing proteins involved in the phototransduction cascade[1]. Age-related increases in iron levels have been found in the human and mouse retinas[4,5]. Disrupted iron homeostasis in hereditary and acquired diseases such as aceruloplasminemia[6], hemochromatosis[7,8], Friedreich’s ataxia[9], diabetic retinopathy (DR)[10], age-related macular degeneration (AMD)[11], glaucoma[12], ocular siderosis[13], multiple blood transfusions[14], and excess dietary iron supplementation[15] have been reported to cause retinal iron accumulation and degeneration. RAS plays an important role in regulating vasoconstriction and electrolyte balance. Angiotensin II (Ang II) is the primary molecule of RAS produced as a result of cleavage of angiotensinogen (AGT) by renin and angiotensin-converting enzyme (ACE)
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