Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina

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...

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Autores principales:	Ashok Mandala, Austin Armstrong, Becky Girresch, Jiyao Zhu, Aruna Chilakala, Sanmathi Chavalmane, Kapil Chaudhary, Pratim Biswas, Judith Ogilvie, Jaya P. Gnana-Prakasam
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/4c589c48032843e4b545e251fc69baee
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spelling	oai:doaj.org-article:4c589c48032843e4b545e251fc69baee2021-12-02T16:05:45ZFenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina10.1038/s41514-020-00050-72056-3973https://doaj.org/article/4c589c48032843e4b545e251fc69baee2020-10-01T00:00:00Zhttps://doi.org/10.1038/s41514-020-00050-7https://doaj.org/toc/2056-3973Abstract 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.Ashok MandalaAustin ArmstrongBecky GirreschJiyao ZhuAruna ChilakalaSanmathi ChavalmaneKapil ChaudharyPratim BiswasJudith OgilvieJaya P. Gnana-PrakasamNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 6, Iss 1, Pp 1-11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Ashok Mandala Austin Armstrong Becky Girresch Jiyao Zhu Aruna Chilakala Sanmathi Chavalmane Kapil Chaudhary Pratim Biswas Judith Ogilvie Jaya P. Gnana-Prakasam Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
description	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.
format	article
author	Ashok Mandala Austin Armstrong Becky Girresch Jiyao Zhu Aruna Chilakala Sanmathi Chavalmane Kapil Chaudhary Pratim Biswas Judith Ogilvie Jaya P. Gnana-Prakasam
author_facet	Ashok Mandala Austin Armstrong Becky Girresch Jiyao Zhu Aruna Chilakala Sanmathi Chavalmane Kapil Chaudhary Pratim Biswas Judith Ogilvie Jaya P. Gnana-Prakasam
author_sort	Ashok Mandala
title	Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
title_short	Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
title_full	Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
title_fullStr	Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
title_full_unstemmed	Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina
title_sort	fenofibrate prevents iron induced activation of canonical wnt/β-catenin and oxidative stress signaling in the retina
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/4c589c48032843e4b545e251fc69baee
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Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina

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