Mitochondrial Dysfunction and Electron Transport Chain Complex Defect in a Rat Model of Tenofovir Disoproxil Fumarate Nephrotoxicity
ABSTRACT The long‐term use of tenofovir, a commonly used anti‐HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF t...
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| Veröffentlicht in: | Journal of biochemical and molecular toxicology 2014-06, Vol.28 (6), p.246-255 |
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| creator | Ramamoorthy, Hemalatha Abraham, Premila Isaac, Bina |
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The long‐term use of tenofovir, a commonly used anti‐HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF treatment on the proximal tubular function, renal mitochondrial function, and the activities of the electron transport chain (ETC) complexes were studied in rats. Damage to proximal tubular mitochondria and proximal tubular dysfunction was observed. The impaired mitochondrial function such as the respiratory control ratio, 2‐(4,5‐dimethyl‐2‐thiazolyl)‐3,5‐diphenyl‐2H‐tetrazolium bromide (MTT) reduction, and mitochondrial swelling was observed. The activities of the electron chain complexes I, II, IV, and V were decreased by 46%, 20%, 26%, and 21%, respectively, in the TDF‐treated rat kidneys. It is suggested that TDF induced proximal tubular mitochondrial dysfunction and ETC defects may impair ATP production, resulting in proximal tubular damage and dysfunction. |
| doi_str_mv | 10.1002/jbt.21560 |
| format | Article |
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The long‐term use of tenofovir, a commonly used anti‐HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF treatment on the proximal tubular function, renal mitochondrial function, and the activities of the electron transport chain (ETC) complexes were studied in rats. Damage to proximal tubular mitochondria and proximal tubular dysfunction was observed. The impaired mitochondrial function such as the respiratory control ratio, 2‐(4,5‐dimethyl‐2‐thiazolyl)‐3,5‐diphenyl‐2H‐tetrazolium bromide (MTT) reduction, and mitochondrial swelling was observed. The activities of the electron chain complexes I, II, IV, and V were decreased by 46%, 20%, 26%, and 21%, respectively, in the TDF‐treated rat kidneys. It is suggested that TDF induced proximal tubular mitochondrial dysfunction and ETC defects may impair ATP production, resulting in proximal tubular damage and dysfunction.</description><identifier>ISSN: 1095-6670</identifier><identifier>EISSN: 1099-0461</identifier><identifier>DOI: 10.1002/jbt.21560</identifier><identifier>PMID: 24615786</identifier><identifier>CODEN: JBMTFQ</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Adenine - analogs & derivatives ; Adenine - toxicity ; Animals ; Anti-HIV Agents - toxicity ; Electron Chain Complexes ; Electron Transport Chain Complex Proteins - metabolism ; Fanconi Syndrome - chemically induced ; Fanconi Syndrome - metabolism ; Human immunodeficiency virus ; Kidney Tubules, Proximal - drug effects ; Kidney Tubules, Proximal - metabolism ; Kidney Tubules, Proximal - pathology ; Male ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondrial DNA ; Mitochondrial Dysfunction ; Mitochondrial Injury ; Mitochondrial Swelling - drug effects ; Organophosphonates - toxicity ; Proteinuria - chemically induced ; Proteinuria - metabolism ; Proximal Tubular Damage ; Rats, Wistar ; Rodents ; Tenofovir ; Tenofovir Disoproxil Fumarate</subject><ispartof>Journal of biochemical and molecular toxicology, 2014-06, Vol.28 (6), p.246-255</ispartof><rights>2014 Wiley Periodicals, Inc.</rights><rights>Copyright © 2014 Wiley Periodicals, Inc., a Wiley Company</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3900-b4f591c3fb801c09f6c279692fc114a81659561891f635b1c9f59e6ad37962593</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjbt.21560$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjbt.21560$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24615786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ramamoorthy, Hemalatha</creatorcontrib><creatorcontrib>Abraham, Premila</creatorcontrib><creatorcontrib>Isaac, Bina</creatorcontrib><title>Mitochondrial Dysfunction and Electron Transport Chain Complex Defect in a Rat Model of Tenofovir Disoproxil Fumarate Nephrotoxicity</title><title>Journal of biochemical and molecular toxicology</title><addtitle>J Biochem Mol Toxicol</addtitle><description>ABSTRACT
The long‐term use of tenofovir, a commonly used anti‐HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF treatment on the proximal tubular function, renal mitochondrial function, and the activities of the electron transport chain (ETC) complexes were studied in rats. Damage to proximal tubular mitochondria and proximal tubular dysfunction was observed. The impaired mitochondrial function such as the respiratory control ratio, 2‐(4,5‐dimethyl‐2‐thiazolyl)‐3,5‐diphenyl‐2H‐tetrazolium bromide (MTT) reduction, and mitochondrial swelling was observed. The activities of the electron chain complexes I, II, IV, and V were decreased by 46%, 20%, 26%, and 21%, respectively, in the TDF‐treated rat kidneys. It is suggested that TDF induced proximal tubular mitochondrial dysfunction and ETC defects may impair ATP production, resulting in proximal tubular damage and dysfunction.</description><subject>Adenine - analogs & derivatives</subject><subject>Adenine - toxicity</subject><subject>Animals</subject><subject>Anti-HIV Agents - toxicity</subject><subject>Electron Chain Complexes</subject><subject>Electron Transport Chain Complex Proteins - metabolism</subject><subject>Fanconi Syndrome - chemically induced</subject><subject>Fanconi Syndrome - metabolism</subject><subject>Human immunodeficiency virus</subject><subject>Kidney Tubules, Proximal - drug effects</subject><subject>Kidney Tubules, Proximal - metabolism</subject><subject>Kidney Tubules, Proximal - pathology</subject><subject>Male</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial DNA</subject><subject>Mitochondrial Dysfunction</subject><subject>Mitochondrial Injury</subject><subject>Mitochondrial Swelling - drug effects</subject><subject>Organophosphonates - toxicity</subject><subject>Proteinuria - chemically induced</subject><subject>Proteinuria - metabolism</subject><subject>Proximal Tubular Damage</subject><subject>Rats, Wistar</subject><subject>Rodents</subject><subject>Tenofovir</subject><subject>Tenofovir Disoproxil Fumarate</subject><issn>1095-6670</issn><issn>1099-0461</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU9v0zAYxiMEYmNw4AsgS1y4ZHttx058hHbdgG1IKMDRclxbdUnjzHagve-D47VjB06c3n-_59VrP0XxGsMpBiBn6y6dEsw4PCmOMQhRQsXx033OSs5rOCpexLgGACZq9rw4InnO6oYfF3fXLnm98sMyONWj-S7aadDJ-QGpYYnOe6NTyEUb1BBHHxKarZQb0Mxvxt5s0dzYTKDcUeirSujaL02PvEWtGbz1v1xAcxf9GPzW9WgxbVRQyaAbM66CT7mpXdq9LJ5Z1Ufz6iGeFN8W5-3ssrz6cvFx9v6q1FQAlF1lmcCa2q4BrEFYrkktuCBWY1ypBnMmGMeNwJZT1mEtMm-4WtJMESboSfHusDefczuZmOTGRW36Xg3GT1FiVgEhFSH0P1DKOGmA3G99-w-69lMY8kP2FDDAAmfqzQM1dRuzlGNw-S928q8VGTg7AL9db3aPcwzy3mOZPZZ7j-WnD-0-yYryoHAxme2jQoWfkte0ZvLHzYX8LBrafl8sJKN_AK1UpxA</recordid><startdate>201406</startdate><enddate>201406</enddate><creator>Ramamoorthy, Hemalatha</creator><creator>Abraham, Premila</creator><creator>Isaac, Bina</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>201406</creationdate><title>Mitochondrial Dysfunction and Electron Transport Chain Complex Defect in a Rat Model of Tenofovir Disoproxil Fumarate Nephrotoxicity</title><author>Ramamoorthy, Hemalatha ; Abraham, Premila ; Isaac, Bina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3900-b4f591c3fb801c09f6c279692fc114a81659561891f635b1c9f59e6ad37962593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adenine - analogs & derivatives</topic><topic>Adenine - toxicity</topic><topic>Animals</topic><topic>Anti-HIV Agents - toxicity</topic><topic>Electron Chain Complexes</topic><topic>Electron Transport Chain Complex Proteins - metabolism</topic><topic>Fanconi Syndrome - chemically induced</topic><topic>Fanconi Syndrome - metabolism</topic><topic>Human immunodeficiency virus</topic><topic>Kidney Tubules, Proximal - drug effects</topic><topic>Kidney Tubules, Proximal - metabolism</topic><topic>Kidney Tubules, Proximal - pathology</topic><topic>Male</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial DNA</topic><topic>Mitochondrial Dysfunction</topic><topic>Mitochondrial Injury</topic><topic>Mitochondrial Swelling - drug effects</topic><topic>Organophosphonates - toxicity</topic><topic>Proteinuria - chemically induced</topic><topic>Proteinuria - metabolism</topic><topic>Proximal Tubular Damage</topic><topic>Rats, Wistar</topic><topic>Rodents</topic><topic>Tenofovir</topic><topic>Tenofovir Disoproxil Fumarate</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ramamoorthy, Hemalatha</creatorcontrib><creatorcontrib>Abraham, Premila</creatorcontrib><creatorcontrib>Isaac, Bina</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of biochemical and molecular toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ramamoorthy, Hemalatha</au><au>Abraham, Premila</au><au>Isaac, Bina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial Dysfunction and Electron Transport Chain Complex Defect in a Rat Model of Tenofovir Disoproxil Fumarate Nephrotoxicity</atitle><jtitle>Journal of biochemical and molecular toxicology</jtitle><addtitle>J Biochem Mol Toxicol</addtitle><date>2014-06</date><risdate>2014</risdate><volume>28</volume><issue>6</issue><spage>246</spage><epage>255</epage><pages>246-255</pages><issn>1095-6670</issn><eissn>1099-0461</eissn><coden>JBMTFQ</coden><abstract>ABSTRACT
The long‐term use of tenofovir, a commonly used anti‐HIV drug, can result in renal damage. The mechanism of tenofovir disoproxil fumarate (TDF) nephrotoxicity is not clear, although it has been shown to target proximal tubular mitochondria. In the present study, the effects of chronic TDF treatment on the proximal tubular function, renal mitochondrial function, and the activities of the electron transport chain (ETC) complexes were studied in rats. Damage to proximal tubular mitochondria and proximal tubular dysfunction was observed. The impaired mitochondrial function such as the respiratory control ratio, 2‐(4,5‐dimethyl‐2‐thiazolyl)‐3,5‐diphenyl‐2H‐tetrazolium bromide (MTT) reduction, and mitochondrial swelling was observed. The activities of the electron chain complexes I, II, IV, and V were decreased by 46%, 20%, 26%, and 21%, respectively, in the TDF‐treated rat kidneys. It is suggested that TDF induced proximal tubular mitochondrial dysfunction and ETC defects may impair ATP production, resulting in proximal tubular damage and dysfunction.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>24615786</pmid><doi>10.1002/jbt.21560</doi><tpages>10</tpages></addata></record> |
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| subjects | Adenine - analogs & derivatives Adenine - toxicity Animals Anti-HIV Agents - toxicity Electron Chain Complexes Electron Transport Chain Complex Proteins - metabolism Fanconi Syndrome - chemically induced Fanconi Syndrome - metabolism Human immunodeficiency virus Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - metabolism Kidney Tubules, Proximal - pathology Male Mitochondria - drug effects Mitochondria - metabolism Mitochondrial DNA Mitochondrial Dysfunction Mitochondrial Injury Mitochondrial Swelling - drug effects Organophosphonates - toxicity Proteinuria - chemically induced Proteinuria - metabolism Proximal Tubular Damage Rats, Wistar Rodents Tenofovir Tenofovir Disoproxil Fumarate |
| title | Mitochondrial Dysfunction and Electron Transport Chain Complex Defect in a Rat Model of Tenofovir Disoproxil Fumarate Nephrotoxicity |
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