非诺贝特阻止铁诱导的典型Wnt/β-连环蛋白和视网膜氧化应激信号的激活。

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
NPJ Aging and Mechanisms of Disease Pub Date : 2020-10-30 eCollection Date: 2020-01-01 DOI:10.1038/s41514-020-00050-7
Ashok Mandala, Austin Armstrong, Becky Girresch, Jiyao Zhu, Aruna Chilakala, Sanmathi Chavalmane, Kapil Chaudhary, Pratim Biswas, Judith Ogilvie, Jaya P Gnana-Prakasam
{"title":"非诺贝特阻止铁诱导的典型Wnt/β-连环蛋白和视网膜氧化应激信号的激活。","authors":"Ashok Mandala,&nbsp;Austin Armstrong,&nbsp;Becky Girresch,&nbsp;Jiyao Zhu,&nbsp;Aruna Chilakala,&nbsp;Sanmathi Chavalmane,&nbsp;Kapil Chaudhary,&nbsp;Pratim Biswas,&nbsp;Judith Ogilvie,&nbsp;Jaya P Gnana-Prakasam","doi":"10.1038/s41514-020-00050-7","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.4000,"publicationDate":"2020-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-00050-7","citationCount":"9","resultStr":"{\"title\":\"Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina.\",\"authors\":\"Ashok Mandala,&nbsp;Austin Armstrong,&nbsp;Becky Girresch,&nbsp;Jiyao Zhu,&nbsp;Aruna Chilakala,&nbsp;Sanmathi Chavalmane,&nbsp;Kapil Chaudhary,&nbsp;Pratim Biswas,&nbsp;Judith Ogilvie,&nbsp;Jaya P Gnana-Prakasam\",\"doi\":\"10.1038/s41514-020-00050-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":19334,\"journal\":{\"name\":\"NPJ Aging and Mechanisms of Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2020-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1038/s41514-020-00050-7\",\"citationCount\":\"9\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Aging and Mechanisms of Disease\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1038/s41514-020-00050-7\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2020/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Aging and Mechanisms of Disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41514-020-00050-7","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2020/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
引用次数: 9

摘要

越来越多的证据有力地表明,铁与衰老和疾病的发病机制有关。研究发现,人和老鼠视网膜中的铁含量都随着年龄的增长而增加。我们和其他人已经表明,视网膜疾病,如年龄相关性黄斑变性和糖尿病性视网膜病变与铁稳态破坏有关,导致视网膜铁积累。此外,由于其中一个铁调节基因突变导致的遗传性疾病导致年龄依赖性视网膜铁过载和变性。然而,我们对铁中毒是否导致视网膜病变的认识有限。最近,我们报道了铁积累与视网膜和肾脏肾素血管紧张素系统(RAS)的上调有关。有证据表明,RAS的多个基因/组分是Wnt/β-catenin信号传导的靶点。有趣的是,在几种退行性疾病中观察到Wnt/β-catenin信号的异常激活。在本研究中,我们探讨了铁积累是否调节视网膜中的典型Wnt信号。我们发现体外和体内铁处理导致视网膜中Wnt/β-catenin信号及其下游靶基因(包括肾素-血管紧张素系统)的上调。我们使用TOPFlash t细胞因子/淋巴细胞增强因子启动子试验和Axin2-LacZ报告小鼠进一步证实了铁激活视网膜中的典型Wnt信号。铁螯合剂或抗氧化剂的存在逆转了铁介导的视网膜色素上皮(RPE)细胞中Wnt/β-catenin信号的上调。此外,用过氧化物酶体增殖激活受体(PPAR) α-激动剂非诺贝特处理RPE细胞可以通过螯合铁来阻止铁诱导的氧化应激和Wnt/β-catenin信号的激活。非诺贝特是一种经fda批准的治疗高脂血症的药物,作为铁螯合剂,对铁相关的退行性疾病具有潜在的重要治疗作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina.

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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
0.00%
发文量
0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信