Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα
Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the patho...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2017-06, Vol.66 (6), p.1671-1682 |
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| container_title | Diabetes (New York, N.Y.) |
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| creator | Chen, Qian Qiu, Fangfang Zhou, Kelu Matlock, H Greg Takahashi, Yusuke Rajala, Raju V S Yang, Yanhui Moran, Elizabeth Ma, Jian-Xing |
| description | Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPARα remains unknown. We investigated the role of
(
) in regulating PPARα in DR.
was overexpressed, while PPARα levels were decreased in the retina of
mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells.
targeted PPARα by inhibiting its mRNA translation. Knockout of
prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of
mice. Intravitreal injection of
inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation in
mice. Further, retinal
levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of
prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of
in the retina is at least partly responsible for PPARα downregulation in DR. Targeting
may represent a novel therapeutic strategy for DR. |
| doi_str_mv | 10.2337/db16-1246 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5440012</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1906456353</sourcerecordid><originalsourceid>FETCH-LOGICAL-c436t-232845440c092cd9e1000382ae5ffab55fd664b30bdd6ab676dc0c5599b443ac3</originalsourceid><addsrcrecordid>eNqFkctKxDAUhoMoOl4WvoAU3OiimnvbjTDMeINBh0HRXUjTdCbSSca0VeaxfBGfyRR1UDcSSBbnO_85-X8A9hE8wYQkp0WOeIww5WughzKSxQQnj-ugByHCMUqyZAts1_UThJCHswm2cIoTyDDqgYexbGZuqq1R0cRVOnJlNDfKu8lNP8YoMjYaGpnrpquH27pFaFhGdzPv2uksGrpX6_W0rWRjnO26x-P-5P1tF2yUsqr13te7A-4vzu8GV_Ho9vJ60B_FihLexJjglDJKoYIZVkWmUViSpFhqVpYyZ6wsOKc5gXlRcJnzhBcKKsayLKeUSEV2wNmn7qLN57pQ2jZeVmLhzVz6pXDSiN8Va2Zi6l5ENzTYEwSOvgS8e2513Yi5qZWuKmm1a2uBMsgp44SR_9E0YRRiTNKAHv5Bn1zrbXAiCJIQGuK8m338SQW_69rrcrU3gqJLVnTJii7ZwB78_OiK_I6SfADRDZ2Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1932331662</pqid></control><display><type>article</type><title>Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Chen, Qian ; Qiu, Fangfang ; Zhou, Kelu ; Matlock, H Greg ; Takahashi, Yusuke ; Rajala, Raju V S ; Yang, Yanhui ; Moran, Elizabeth ; Ma, Jian-Xing</creator><creatorcontrib>Chen, Qian ; Qiu, Fangfang ; Zhou, Kelu ; Matlock, H Greg ; Takahashi, Yusuke ; Rajala, Raju V S ; Yang, Yanhui ; Moran, Elizabeth ; Ma, Jian-Xing</creatorcontrib><description>Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPARα remains unknown. We investigated the role of
(
) in regulating PPARα in DR.
was overexpressed, while PPARα levels were decreased in the retina of
mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells.
targeted PPARα by inhibiting its mRNA translation. Knockout of
prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of
mice. Intravitreal injection of
inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation in
mice. Further, retinal
levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of
prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of
in the retina is at least partly responsible for PPARα downregulation in DR. Targeting
may represent a novel therapeutic strategy for DR.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db16-1246</identifier><identifier>PMID: 28270521</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Animals ; Apoptosis ; Apoptosis - genetics ; Blotting, Western ; Cell Line ; Cells, Cultured ; Complications ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - genetics ; Diabetes Mellitus, Type 2 - metabolism ; Diabetic retinopathy ; Diabetic Retinopathy - genetics ; Diabetic Retinopathy - metabolism ; Disease Models, Animal ; Down-Regulation ; Endothelial cells ; Fenofibrate ; Humans ; Inflammation ; Mice ; Mice, Knockout ; MicroRNAs ; MicroRNAs - genetics ; Microvasculature ; miRNA ; mRNA ; Oxygen ; Palmitic acid ; Pathogenesis ; Peroxisome proliferator-activated receptor-a ; PPAR alpha - genetics ; Real-Time Polymerase Chain Reaction ; Retina ; Retina - metabolism ; Retinal Neovascularization - genetics ; Retinal Pigment Epithelium - cytology ; Retinopathy ; Reverse Transcriptase Polymerase Chain Reaction ; Rodents ; Vascularization</subject><ispartof>Diabetes (New York, N.Y.), 2017-06, Vol.66 (6), p.1671-1682</ispartof><rights>2017 by the American Diabetes Association.</rights><rights>Copyright American Diabetes Association Jun 1, 2017</rights><rights>2017 by the American Diabetes Association. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-232845440c092cd9e1000382ae5ffab55fd664b30bdd6ab676dc0c5599b443ac3</citedby><cites>FETCH-LOGICAL-c436t-232845440c092cd9e1000382ae5ffab55fd664b30bdd6ab676dc0c5599b443ac3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440012/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440012/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28270521$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Qian</creatorcontrib><creatorcontrib>Qiu, Fangfang</creatorcontrib><creatorcontrib>Zhou, Kelu</creatorcontrib><creatorcontrib>Matlock, H Greg</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Rajala, Raju V S</creatorcontrib><creatorcontrib>Yang, Yanhui</creatorcontrib><creatorcontrib>Moran, Elizabeth</creatorcontrib><creatorcontrib>Ma, Jian-Xing</creatorcontrib><title>Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPARα remains unknown. We investigated the role of
(
) in regulating PPARα in DR.
was overexpressed, while PPARα levels were decreased in the retina of
mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells.
targeted PPARα by inhibiting its mRNA translation. Knockout of
prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of
mice. Intravitreal injection of
inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation in
mice. Further, retinal
levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of
prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of
in the retina is at least partly responsible for PPARα downregulation in DR. Targeting
may represent a novel therapeutic strategy for DR.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Cells, Cultured</subject><subject>Complications</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - genetics</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetic retinopathy</subject><subject>Diabetic Retinopathy - genetics</subject><subject>Diabetic Retinopathy - metabolism</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation</subject><subject>Endothelial cells</subject><subject>Fenofibrate</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>Microvasculature</subject><subject>miRNA</subject><subject>mRNA</subject><subject>Oxygen</subject><subject>Palmitic acid</subject><subject>Pathogenesis</subject><subject>Peroxisome proliferator-activated receptor-a</subject><subject>PPAR alpha - genetics</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Retina</subject><subject>Retina - metabolism</subject><subject>Retinal Neovascularization - genetics</subject><subject>Retinal Pigment Epithelium - cytology</subject><subject>Retinopathy</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Rodents</subject><subject>Vascularization</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctKxDAUhoMoOl4WvoAU3OiimnvbjTDMeINBh0HRXUjTdCbSSca0VeaxfBGfyRR1UDcSSBbnO_85-X8A9hE8wYQkp0WOeIww5WughzKSxQQnj-ugByHCMUqyZAts1_UThJCHswm2cIoTyDDqgYexbGZuqq1R0cRVOnJlNDfKu8lNP8YoMjYaGpnrpquH27pFaFhGdzPv2uksGrpX6_W0rWRjnO26x-P-5P1tF2yUsqr13te7A-4vzu8GV_Ho9vJ60B_FihLexJjglDJKoYIZVkWmUViSpFhqVpYyZ6wsOKc5gXlRcJnzhBcKKsayLKeUSEV2wNmn7qLN57pQ2jZeVmLhzVz6pXDSiN8Va2Zi6l5ENzTYEwSOvgS8e2513Yi5qZWuKmm1a2uBMsgp44SR_9E0YRRiTNKAHv5Bn1zrbXAiCJIQGuK8m338SQW_69rrcrU3gqJLVnTJii7ZwB78_OiK_I6SfADRDZ2Q</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Chen, Qian</creator><creator>Qiu, Fangfang</creator><creator>Zhou, Kelu</creator><creator>Matlock, H Greg</creator><creator>Takahashi, Yusuke</creator><creator>Rajala, Raju V S</creator><creator>Yang, Yanhui</creator><creator>Moran, Elizabeth</creator><creator>Ma, Jian-Xing</creator><general>American Diabetes Association</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20170601</creationdate><title>Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα</title><author>Chen, Qian ; Qiu, Fangfang ; Zhou, Kelu ; Matlock, H Greg ; Takahashi, Yusuke ; Rajala, Raju V S ; Yang, Yanhui ; Moran, Elizabeth ; Ma, Jian-Xing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-232845440c092cd9e1000382ae5ffab55fd664b30bdd6ab676dc0c5599b443ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Cells, Cultured</topic><topic>Complications</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - genetics</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetic retinopathy</topic><topic>Diabetic Retinopathy - genetics</topic><topic>Diabetic Retinopathy - metabolism</topic><topic>Disease Models, Animal</topic><topic>Down-Regulation</topic><topic>Endothelial cells</topic><topic>Fenofibrate</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>Microvasculature</topic><topic>miRNA</topic><topic>mRNA</topic><topic>Oxygen</topic><topic>Palmitic acid</topic><topic>Pathogenesis</topic><topic>Peroxisome proliferator-activated receptor-a</topic><topic>PPAR alpha - genetics</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Retina</topic><topic>Retina - metabolism</topic><topic>Retinal Neovascularization - genetics</topic><topic>Retinal Pigment Epithelium - cytology</topic><topic>Retinopathy</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Rodents</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Qian</creatorcontrib><creatorcontrib>Qiu, Fangfang</creatorcontrib><creatorcontrib>Zhou, Kelu</creatorcontrib><creatorcontrib>Matlock, H Greg</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Rajala, Raju V S</creatorcontrib><creatorcontrib>Yang, Yanhui</creatorcontrib><creatorcontrib>Moran, Elizabeth</creatorcontrib><creatorcontrib>Ma, Jian-Xing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Qian</au><au>Qiu, Fangfang</au><au>Zhou, Kelu</au><au>Matlock, H Greg</au><au>Takahashi, Yusuke</au><au>Rajala, Raju V S</au><au>Yang, Yanhui</au><au>Moran, Elizabeth</au><au>Ma, Jian-Xing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>66</volume><issue>6</issue><spage>1671</spage><epage>1682</epage><pages>1671-1682</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor-α (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in patients with type 2 diabetes. Our recent studies have shown that PPARα is downregulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced downregulation of PPARα remains unknown. We investigated the role of
(
) in regulating PPARα in DR.
was overexpressed, while PPARα levels were decreased in the retina of
mice, a model of type 2 diabetes. Such alterations were also observed in palmitate-treated retinal endothelial cells.
targeted PPARα by inhibiting its mRNA translation. Knockout of
prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation, and reduced cell apoptosis in the retina of
mice. Intravitreal injection of
inhibitor attenuated PPARα downregulation and ameliorated retinal inflammation in
mice. Further, retinal
levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of
prevented PPARα downregulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced overexpression of
in the retina is at least partly responsible for PPARα downregulation in DR. Targeting
may represent a novel therapeutic strategy for DR.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>28270521</pmid><doi>10.2337/db16-1246</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Animals Apoptosis Apoptosis - genetics Blotting, Western Cell Line Cells, Cultured Complications Diabetes Diabetes mellitus Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Diabetic retinopathy Diabetic Retinopathy - genetics Diabetic Retinopathy - metabolism Disease Models, Animal Down-Regulation Endothelial cells Fenofibrate Humans Inflammation Mice Mice, Knockout MicroRNAs MicroRNAs - genetics Microvasculature miRNA mRNA Oxygen Palmitic acid Pathogenesis Peroxisome proliferator-activated receptor-a PPAR alpha - genetics Real-Time Polymerase Chain Reaction Retina Retina - metabolism Retinal Neovascularization - genetics Retinal Pigment Epithelium - cytology Retinopathy Reverse Transcriptase Polymerase Chain Reaction Rodents Vascularization |
| title | Pathogenic Role of microRNA-21 in Diabetic Retinopathy Through Downregulation of PPARα |
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