Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling
The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (R...
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| creator | Guo, Kaifeng Lu, Junxi Huang, Yan Wu, Mian Zhang, Lei Yu, Haoyong Zhang, Mingliang Bao, Yuqian He, John Cijiang Chen, Haibing Jia, Weiping |
| description | The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1α, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1α. These data suggest that PGC-1α may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN. |
| doi_str_mv | 10.1371/journal.pone.0125176 |
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However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1α, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1α. These data suggest that PGC-1α may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0125176</identifier><identifier>PMID: 25853493</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>8-Hydroxy-2'-Deoxyguanosine ; 8-Hydroxydeoxyguanosine ; Animals ; Apoptosis ; Bioindicators ; Biomarkers ; Biomarkers - metabolism ; Biosynthesis ; Deoxyguanosine - analogs & derivatives ; Deoxyguanosine - metabolism ; Diabetes ; Diabetes mellitus ; Diabetic Nephropathies - genetics ; Diabetic Nephropathies - metabolism ; Diabetic Nephropathies - pathology ; Diabetic nephropathy ; Dynamins - genetics ; Dynamins - metabolism ; Endocrinology ; Gene expression ; Gene Expression Regulation ; Glucose ; Glucose - metabolism ; Glucose - pharmacology ; Hospitals ; Humans ; Hyperglycemia ; Hyperglycemia - genetics ; Hyperglycemia - metabolism ; Hyperglycemia - pathology ; Hypertrophy ; Inhibition ; Kidneys ; Laboratory animals ; Male ; Mesangial cells ; Mesangial Cells - drug effects ; Mesangial Cells - metabolism ; Mesangial Cells - pathology ; Metabolism ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial Dynamics - drug effects ; Mitochondrial Dynamics - genetics ; Morphology ; Nephropathy ; Oxidative Stress ; Oxygen ; Pathogenesis ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Plasmids - chemistry ; Plasmids - metabolism ; Primary Cell Culture ; Proteins ; Proteinuria ; Rats ; Rats, Sprague-Dawley ; Reactive oxygen species ; Reactive Oxygen Species - antagonists & inhibitors ; Reactive Oxygen Species - metabolism ; Renal cortex ; Rodents ; Signal Transduction ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transfection</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0125176-e0125176</ispartof><rights>2015 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Guo et al 2015 Guo et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-806f3e86f135a17e54db1bf464cd9151c9a5bb3dbd8aee8175196a56252954293</citedby><cites>FETCH-LOGICAL-c526t-806f3e86f135a17e54db1bf464cd9151c9a5bb3dbd8aee8175196a56252954293</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/PMC4390193/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390193/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25853493$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ushio-Fukai, Masuko</contributor><creatorcontrib>Guo, Kaifeng</creatorcontrib><creatorcontrib>Lu, Junxi</creatorcontrib><creatorcontrib>Huang, Yan</creatorcontrib><creatorcontrib>Wu, Mian</creatorcontrib><creatorcontrib>Zhang, Lei</creatorcontrib><creatorcontrib>Yu, Haoyong</creatorcontrib><creatorcontrib>Zhang, Mingliang</creatorcontrib><creatorcontrib>Bao, Yuqian</creatorcontrib><creatorcontrib>He, John Cijiang</creatorcontrib><creatorcontrib>Chen, Haibing</creatorcontrib><creatorcontrib>Jia, Weiping</creatorcontrib><title>Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1α, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1α. These data suggest that PGC-1α may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN.</description><subject>8-Hydroxy-2'-Deoxyguanosine</subject><subject>8-Hydroxydeoxyguanosine</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Bioindicators</subject><subject>Biomarkers</subject><subject>Biomarkers - metabolism</subject><subject>Biosynthesis</subject><subject>Deoxyguanosine - analogs & derivatives</subject><subject>Deoxyguanosine - metabolism</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetic Nephropathies - genetics</subject><subject>Diabetic Nephropathies - metabolism</subject><subject>Diabetic Nephropathies - pathology</subject><subject>Diabetic nephropathy</subject><subject>Dynamins - genetics</subject><subject>Dynamins - metabolism</subject><subject>Endocrinology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Glucose - pharmacology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - genetics</subject><subject>Hyperglycemia - metabolism</subject><subject>Hyperglycemia - pathology</subject><subject>Hypertrophy</subject><subject>Inhibition</subject><subject>Kidneys</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Mesangial cells</subject><subject>Mesangial Cells - drug effects</subject><subject>Mesangial Cells - metabolism</subject><subject>Mesangial Cells - pathology</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial Dynamics - drug effects</subject><subject>Mitochondrial Dynamics - genetics</subject><subject>Morphology</subject><subject>Nephropathy</subject><subject>Oxidative Stress</subject><subject>Oxygen</subject><subject>Pathogenesis</subject><subject>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha</subject><subject>Plasmids - chemistry</subject><subject>Plasmids - metabolism</subject><subject>Primary Cell Culture</subject><subject>Proteins</subject><subject>Proteinuria</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - antagonists & inhibitors</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Renal cortex</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptkstuEzEUhkcIREvhDRBYYsMmwZexZ7xBQhGUSpVacVlbvpzJOJqxg-0UZd8X6ovwTEyatGoRK1vH__nOxX9VvSZ4TlhDPqziJgU9zNcxwBwTykkjnlTHRDI6ExSzpw_uR9WLnFcYc9YK8bw6orzlrJbsuLq-TLGALf4KUIoDoNihy9PFjPy5QT4g57WB4i0KsO5TXOvSb5HPSOccrdcFHPrtS49KD5O898YXH8MO8u3i-xRNcbPs0ehLtH0MLnk9ILcNepyQCcboYPBh-bJ61ukhw6vDeVL9_PL5x-Lr7Pzi9Gzx6XxmORVl1mLRMWhFRxjXpAFeO0NMV4vaOkk4sVJzY5gzrtUALWk4kUJzQTmVvKaSnVRv99z1ELM6LDArIhpCcdPKdlKc7RUu6pVaJz_qtFVRe3UbiGmpdJr2MYCyHThDnZUNk3UrjGwwNZQagaXArDMT6-Oh2saM4CyEkvTwCPr4JfheLeOVqpnE09dNgPcHQIq_NpCLGn22MAw6QNzc9k0FFm3TTNJ3_0j_P129V9kUc07Q3TdDsNqZ6i5L7UylDqaa0t48HOQ-6c5F7C-EUc0X</recordid><startdate>20150408</startdate><enddate>20150408</enddate><creator>Guo, Kaifeng</creator><creator>Lu, Junxi</creator><creator>Huang, Yan</creator><creator>Wu, Mian</creator><creator>Zhang, Lei</creator><creator>Yu, Haoyong</creator><creator>Zhang, Mingliang</creator><creator>Bao, Yuqian</creator><creator>He, John Cijiang</creator><creator>Chen, Haibing</creator><creator>Jia, Weiping</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150408</creationdate><title>Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling</title><author>Guo, Kaifeng ; Lu, Junxi ; Huang, Yan ; Wu, Mian ; Zhang, Lei ; Yu, Haoyong ; Zhang, Mingliang ; Bao, Yuqian ; He, John Cijiang ; Chen, Haibing ; Jia, Weiping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-806f3e86f135a17e54db1bf464cd9151c9a5bb3dbd8aee8175196a56252954293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>8-Hydroxy-2'-Deoxyguanosine</topic><topic>8-Hydroxydeoxyguanosine</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Bioindicators</topic><topic>Biomarkers</topic><topic>Biomarkers - metabolism</topic><topic>Biosynthesis</topic><topic>Deoxyguanosine - analogs & derivatives</topic><topic>Deoxyguanosine - metabolism</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetic Nephropathies - genetics</topic><topic>Diabetic Nephropathies - metabolism</topic><topic>Diabetic Nephropathies - pathology</topic><topic>Diabetic nephropathy</topic><topic>Dynamins - genetics</topic><topic>Dynamins - metabolism</topic><topic>Endocrinology</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Glucose - pharmacology</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Hyperglycemia - genetics</topic><topic>Hyperglycemia - metabolism</topic><topic>Hyperglycemia - pathology</topic><topic>Hypertrophy</topic><topic>Inhibition</topic><topic>Kidneys</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>Mesangial cells</topic><topic>Mesangial Cells - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guo, Kaifeng</au><au>Lu, Junxi</au><au>Huang, Yan</au><au>Wu, Mian</au><au>Zhang, Lei</au><au>Yu, Haoyong</au><au>Zhang, Mingliang</au><au>Bao, Yuqian</au><au>He, John Cijiang</au><au>Chen, Haibing</au><au>Jia, Weiping</au><au>Ushio-Fukai, Masuko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-08</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0125176</spage><epage>e0125176</epage><pages>e0125176-e0125176</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The overproduction of mitochondrial reactive oxygen species (ROS) plays a key role in the pathogenesis of diabetic nephropathy (DN). However, the underlying molecular mechanism remains unclear. Our aim was to investigate the role of PGC-1α in the pathogenesis of DN. Rat glomerular mesangial cells (RMCs) were incubated in normal or high glucose medium with or without the PGC-1α-overexpressing plasmid (pcDNA3-PGC-1α) for 48 h. In the diabetic rats, decreased PGC-1α expression was associated with increased mitochondrial ROS generation in the renal cortex, increased proteinuria, glomerular hypertrophy, and higher glomerular 8-OHdG (a biomarker for oxidative stress). In vitro, hyperglycemia induced the downregulation of PGC-1α, which led to increased DRP1 expression, increased mitochondrial fragmentation and damaged network structure. This was associated with an increase in ROS generation and mesangial cell hypertrophy. These pathological changes were reversed in vitro by the transfection of pcDNA3-PGC-1α. These data suggest that PGC-1α may protect DN via the inhibition of DRP1-mediated mitochondrial dynamic remodeling and ROS production. These findings may assist the development of novel therapeutic strategies for patients with DN.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25853493</pmid><doi>10.1371/journal.pone.0125176</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1671207898 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 8-Hydroxy-2'-Deoxyguanosine 8-Hydroxydeoxyguanosine Animals Apoptosis Bioindicators Biomarkers Biomarkers - metabolism Biosynthesis Deoxyguanosine - analogs & derivatives Deoxyguanosine - metabolism Diabetes Diabetes mellitus Diabetic Nephropathies - genetics Diabetic Nephropathies - metabolism Diabetic Nephropathies - pathology Diabetic nephropathy Dynamins - genetics Dynamins - metabolism Endocrinology Gene expression Gene Expression Regulation Glucose Glucose - metabolism Glucose - pharmacology Hospitals Humans Hyperglycemia Hyperglycemia - genetics Hyperglycemia - metabolism Hyperglycemia - pathology Hypertrophy Inhibition Kidneys Laboratory animals Male Mesangial cells Mesangial Cells - drug effects Mesangial Cells - metabolism Mesangial Cells - pathology Metabolism Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Mitochondrial Dynamics - drug effects Mitochondrial Dynamics - genetics Morphology Nephropathy Oxidative Stress Oxygen Pathogenesis Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Plasmids - chemistry Plasmids - metabolism Primary Cell Culture Proteins Proteinuria Rats Rats, Sprague-Dawley Reactive oxygen species Reactive Oxygen Species - antagonists & inhibitors Reactive Oxygen Species - metabolism Renal cortex Rodents Signal Transduction Transcription Factors - genetics Transcription Factors - metabolism Transfection |
| title | Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-29T13%3A33%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Protective%20role%20of%20PGC-1%CE%B1%20in%20diabetic%20nephropathy%20is%20associated%20with%20the%20inhibition%20of%20ROS%20through%20mitochondrial%20dynamic%20remodeling&rft.jtitle=PloS%20one&rft.au=Guo,%20Kaifeng&rft.date=2015-04-08&rft.volume=10&rft.issue=4&rft.spage=e0125176&rft.epage=e0125176&rft.pages=e0125176-e0125176&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0125176&rft_dat=%3Cproquest_plos_%3E1672606877%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1671207898&rft_id=info:pmid/25853493&rft_doaj_id=oai_doaj_org_article_cfedb2dc9739486b9702b22b609603fb&rfr_iscdi=true |