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High glucose‐induced changes in hyaloid‐retinal vessels during early ocular development of zebrafish: a short‐term animal model of diabetic retinopathy

Background and Purpose Although a variety of animal models have been used to test drug candidates and examine the pathogenesis of diabetic retinopathy, time‐saving and inexpensive models are still needed to evaluate the increasing number of therapeutic approaches. Experimental Approach We developed...

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Published in:British journal of pharmacology 2016-01, Vol.173 (1), p.15-26
Main Authors: Jung, Seung‐Hyun, Kim, Young Sook, Lee, Yu‐Ri, Kim, Jin Sook
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Kim, Young Sook
Lee, Yu‐Ri
Kim, Jin Sook
description Background and Purpose Although a variety of animal models have been used to test drug candidates and examine the pathogenesis of diabetic retinopathy, time‐saving and inexpensive models are still needed to evaluate the increasing number of therapeutic approaches. Experimental Approach We developed a model for diabetic retinopathy using the early stage of transgenic zebrafish (flk:EGFP) by treating embryos with 130 mM glucose, from 3‐6 days post fertilisation (high‐glucose model). On day 6, lenses from zebrafish larvae were isolated and treated with 3% trypsin, and changes in hyaloid‐retinal vessels were analysed using fluorescent stereomicroscopy. In addition, expression of tight junction proteins (such as zonula occludens‐1), effects of hyperosmolar solutions and of hypoxia, and Vegf expression were assessed by RT –PCR. NO production was assessed with a fluorescent substrate. Effects of inhibitors of the VEGF receptor, NO synthesis and a VEGF antibody (ranibizumab) were also measured. Key Results In this high‐glucose model, dilation of hyaloid‐retinal vessels, on day 6, was accompanied by morphological lesions with disruption of tight junction proteins, overproduction of Vegf mRNA and increased NO production. Treatment of this high‐glucose model with an inhibitor of VEGF receptor tyrosine kinase or an inhibitor of NO synthase or ranibizumab decreased dilation of hyaloid‐retinal vessels. Conclusions and Implications These findings suggest that short‐term exposure of zebrafish larvae to high‐glucose conditions could be used for screening and drug discovery for diabetic retinopathy and particularly for disorders of retinal vessels related to disruption of tight junction proteins and excessive VEGF and NO production.
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Experimental Approach We developed a model for diabetic retinopathy using the early stage of transgenic zebrafish (flk:EGFP) by treating embryos with 130 mM glucose, from 3‐6 days post fertilisation (high‐glucose model). On day 6, lenses from zebrafish larvae were isolated and treated with 3% trypsin, and changes in hyaloid‐retinal vessels were analysed using fluorescent stereomicroscopy. In addition, expression of tight junction proteins (such as zonula occludens‐1), effects of hyperosmolar solutions and of hypoxia, and Vegf expression were assessed by RT –PCR. NO production was assessed with a fluorescent substrate. Effects of inhibitors of the VEGF receptor, NO synthesis and a VEGF antibody (ranibizumab) were also measured. Key Results In this high‐glucose model, dilation of hyaloid‐retinal vessels, on day 6, was accompanied by morphological lesions with disruption of tight junction proteins, overproduction of Vegf mRNA and increased NO production. Treatment of this high‐glucose model with an inhibitor of VEGF receptor tyrosine kinase or an inhibitor of NO synthase or ranibizumab decreased dilation of hyaloid‐retinal vessels. 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Experimental Approach We developed a model for diabetic retinopathy using the early stage of transgenic zebrafish (flk:EGFP) by treating embryos with 130 mM glucose, from 3‐6 days post fertilisation (high‐glucose model). On day 6, lenses from zebrafish larvae were isolated and treated with 3% trypsin, and changes in hyaloid‐retinal vessels were analysed using fluorescent stereomicroscopy. In addition, expression of tight junction proteins (such as zonula occludens‐1), effects of hyperosmolar solutions and of hypoxia, and Vegf expression were assessed by RT –PCR. NO production was assessed with a fluorescent substrate. Effects of inhibitors of the VEGF receptor, NO synthesis and a VEGF antibody (ranibizumab) were also measured. Key Results In this high‐glucose model, dilation of hyaloid‐retinal vessels, on day 6, was accompanied by morphological lesions with disruption of tight junction proteins, overproduction of Vegf mRNA and increased NO production. Treatment of this high‐glucose model with an inhibitor of VEGF receptor tyrosine kinase or an inhibitor of NO synthase or ranibizumab decreased dilation of hyaloid‐retinal vessels. Conclusions and Implications These findings suggest that short‐term exposure of zebrafish larvae to high‐glucose conditions could be used for screening and drug discovery for diabetic retinopathy and particularly for disorders of retinal vessels related to disruption of tight junction proteins and excessive VEGF and NO production.</description><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Danio rerio</subject><subject>Diabetes</subject><subject>Diabetic retinopathy</subject><subject>Diabetic Retinopathy - chemically induced</subject><subject>Diabetic Retinopathy - metabolism</subject><subject>Disease Models, Animal</subject><subject>Glucose - adverse effects</subject><subject>Kinases</subject><subject>Larva - drug effects</subject><subject>Larva - metabolism</subject><subject>NG-Nitroarginine Methyl Ester - pharmacology</subject><subject>Nitric Oxide - biosynthesis</subject><subject>Proteins</subject><subject>Ranibizumab - pharmacology</subject><subject>Receptors, Vascular Endothelial Growth Factor - metabolism</subject><subject>Research Paper</subject><subject>Research Papers</subject><subject>Retinal Vessels - drug effects</subject><subject>Retinal Vessels - metabolism</subject><subject>Retinal Vessels - pathology</subject><subject>Tight Junction Proteins - metabolism</subject><subject>Vascular Endothelial Growth Factor A - biosynthesis</subject><subject>Zebrafish - growth &amp; 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development</topic><topic>Zebrafish - metabolism</topic><topic>Zebrafish Proteins - biosynthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jung, Seung‐Hyun</creatorcontrib><creatorcontrib>Kim, Young Sook</creatorcontrib><creatorcontrib>Lee, Yu‐Ri</creatorcontrib><creatorcontrib>Kim, Jin Sook</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jung, Seung‐Hyun</au><au>Kim, Young Sook</au><au>Lee, Yu‐Ri</au><au>Kim, Jin Sook</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High glucose‐induced changes in hyaloid‐retinal vessels during early ocular development of zebrafish: a short‐term animal model of diabetic retinopathy</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2016-01</date><risdate>2016</risdate><volume>173</volume><issue>1</issue><spage>15</spage><epage>26</epage><pages>15-26</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><abstract>Background and Purpose Although a variety of animal models have been used to test drug candidates and examine the pathogenesis of diabetic retinopathy, time‐saving and inexpensive models are still needed to evaluate the increasing number of therapeutic approaches. Experimental Approach We developed a model for diabetic retinopathy using the early stage of transgenic zebrafish (flk:EGFP) by treating embryos with 130 mM glucose, from 3‐6 days post fertilisation (high‐glucose model). On day 6, lenses from zebrafish larvae were isolated and treated with 3% trypsin, and changes in hyaloid‐retinal vessels were analysed using fluorescent stereomicroscopy. In addition, expression of tight junction proteins (such as zonula occludens‐1), effects of hyperosmolar solutions and of hypoxia, and Vegf expression were assessed by RT –PCR. NO production was assessed with a fluorescent substrate. Effects of inhibitors of the VEGF receptor, NO synthesis and a VEGF antibody (ranibizumab) were also measured. Key Results In this high‐glucose model, dilation of hyaloid‐retinal vessels, on day 6, was accompanied by morphological lesions with disruption of tight junction proteins, overproduction of Vegf mRNA and increased NO production. Treatment of this high‐glucose model with an inhibitor of VEGF receptor tyrosine kinase or an inhibitor of NO synthase or ranibizumab decreased dilation of hyaloid‐retinal vessels. Conclusions and Implications These findings suggest that short‐term exposure of zebrafish larvae to high‐glucose conditions could be used for screening and drug discovery for diabetic retinopathy and particularly for disorders of retinal vessels related to disruption of tight junction proteins and excessive VEGF and NO production.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>26276677</pmid><doi>10.1111/bph.13279</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0007-1188
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source PubMed Central (Open Access); Wiley
subjects Animals
Animals, Genetically Modified
Danio rerio
Diabetes
Diabetic retinopathy
Diabetic Retinopathy - chemically induced
Diabetic Retinopathy - metabolism
Disease Models, Animal
Glucose - adverse effects
Kinases
Larva - drug effects
Larva - metabolism
NG-Nitroarginine Methyl Ester - pharmacology
Nitric Oxide - biosynthesis
Proteins
Ranibizumab - pharmacology
Receptors, Vascular Endothelial Growth Factor - metabolism
Research Paper
Research Papers
Retinal Vessels - drug effects
Retinal Vessels - metabolism
Retinal Vessels - pathology
Tight Junction Proteins - metabolism
Vascular Endothelial Growth Factor A - biosynthesis
Zebrafish - growth & development
Zebrafish - metabolism
Zebrafish Proteins - biosynthesis
title High glucose‐induced changes in hyaloid‐retinal vessels during early ocular development of zebrafish: a short‐term animal model of diabetic retinopathy
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