Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity
Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductas...
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| creator | Jaikumkao, Krit Pongchaidecha, Anchalee Thongnak, La-Ongdao Wanchai, Keerati Arjinajarn, Phatchawan Chatsudthipong, Varanuj Chattipakorn, Nipon Lungkaphin, Anusorn |
| description | Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment. |
| doi_str_mv | 10.1371/journal.pone.0164528 |
| format | Article |
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However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0164528</identifier><identifier>PMID: 27727327</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aminoglycoside antibiotics ; Aminoglycosides ; Animals ; Antibiotics ; Antioxidants ; Apoptosis ; Apoptosis - drug effects ; Atorvastatin ; Atorvastatin Calcium - pharmacology ; Atorvastatin Calcium - therapeutic use ; Attenuation ; Bcl-2 protein ; bcl-2-Associated X Protein - metabolism ; Biology and Life Sciences ; Blood Urea Nitrogen ; Calpain ; Caspase ; Caspase 12 - metabolism ; Caspase-12 ; Caspase-3 ; Cell cycle ; Coenzyme A ; Creatinine ; Creatinine - blood ; Cytokines ; Diabetes ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug dosages ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - drug effects ; Fibrosis ; Gangrene ; Gentamicin ; Gentamicins - toxicity ; Health aspects ; Heart failure ; Heat-Shock Proteins - metabolism ; Hydroxymethylglutaryl-CoA reductase ; Hypertrophy ; Inflammation ; Injection ; Interleukin 6 ; Interleukin-6 - metabolism ; Kidney - drug effects ; Kidney - metabolism ; Kidney - pathology ; Kidneys ; Laboratory animals ; Male ; Medicine ; Medicine and Health Sciences ; Nephritis - chemically induced ; Nephritis - pathology ; Nephritis - prevention & control ; NF-kappa B - metabolism ; NF-κB protein ; Nitric Oxide Synthase Type II - metabolism ; Nitric-oxide synthase ; Oxidative stress ; Physiology ; Protective Agents - pharmacology ; Protective Agents - therapeutic use ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Rats ; Rats, Sprague-Dawley ; Renal function ; Research and Analysis Methods ; Rodents ; Stress response ; Transforming Growth Factor beta1 - metabolism ; Transforming growth factor-b1 ; Transforming growth factors ; Tumor necrosis factor-TNF ; Urea</subject><ispartof>PloS one, 2016-10, Vol.11 (10), p.e0164528</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Jaikumkao 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>2016 Jaikumkao et al 2016 Jaikumkao et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-8f53d3122dfb32aa810c4fe474298ea6a268de5c83887344a1b9f20406ff70cf3</citedby><cites>FETCH-LOGICAL-c725t-8f53d3122dfb32aa810c4fe474298ea6a268de5c83887344a1b9f20406ff70cf3</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/PMC5058561/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058561/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27727327$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jaikumkao, Krit</creatorcontrib><creatorcontrib>Pongchaidecha, Anchalee</creatorcontrib><creatorcontrib>Thongnak, La-Ongdao</creatorcontrib><creatorcontrib>Wanchai, Keerati</creatorcontrib><creatorcontrib>Arjinajarn, Phatchawan</creatorcontrib><creatorcontrib>Chatsudthipong, Varanuj</creatorcontrib><creatorcontrib>Chattipakorn, Nipon</creatorcontrib><creatorcontrib>Lungkaphin, Anusorn</creatorcontrib><title>Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.</description><subject>Aminoglycoside antibiotics</subject><subject>Aminoglycosides</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Antioxidants</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Atorvastatin</subject><subject>Atorvastatin Calcium - pharmacology</subject><subject>Atorvastatin Calcium - therapeutic use</subject><subject>Attenuation</subject><subject>Bcl-2 protein</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Biology and Life Sciences</subject><subject>Blood Urea Nitrogen</subject><subject>Calpain</subject><subject>Caspase</subject><subject>Caspase 12 - metabolism</subject><subject>Caspase-12</subject><subject>Caspase-3</subject><subject>Cell cycle</subject><subject>Coenzyme A</subject><subject>Creatinine</subject><subject>Creatinine - blood</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Drug dosages</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Fibrosis</subject><subject>Gangrene</subject><subject>Gentamicin</subject><subject>Gentamicins - toxicity</subject><subject>Health aspects</subject><subject>Heart failure</subject><subject>Heat-Shock Proteins - metabolism</subject><subject>Hydroxymethylglutaryl-CoA reductase</subject><subject>Hypertrophy</subject><subject>Inflammation</subject><subject>Injection</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidneys</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Nephritis - chemically induced</subject><subject>Nephritis - pathology</subject><subject>Nephritis - prevention & control</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Oxidative stress</subject><subject>Physiology</subject><subject>Protective Agents - pharmacology</subject><subject>Protective Agents - therapeutic use</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Renal function</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Stress response</subject><subject>Transforming Growth Factor beta1 - metabolism</subject><subject>Transforming growth factor-b1</subject><subject>Transforming growth factors</subject><subject>Tumor necrosis factor-TNF</subject><subject>Urea</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk21r1TAUx4sobk6_gWhAEAXvtUnbNH0jXOacF4aTzfk2pOnJvRlpUpN0bh_Lb2i63Y1d2QtpocnJ7_xPcx6y7CXO57io8cdzN3orzHxwFuY5pmVF2KNsFzcFmVGSF4_vrXeyZyGc53lVMEqfZjukrkldkHo3-7PowWjnRdTOIqfQCSRRtLTKiL6_tn5AB7ZzgxGh1zKdRy1HM_boNHoIAQnbocXghuiCDujMduCNhoDiGtB37yLIqC8AHSiVVlOEI_cbfXZBrGDaLaLzFyLEFMqi9B6CjSIF0na2tN0ooUPfYFgnIXeZrPHqefZECRPgxea7l519Ofix_3V2dHy43F8czWRNqjhjqiq6AhPSqbYgQjCcy1JBWZekYSCoIJR1UElWMFYXZSlw2yiSlzlVqs6lKvay1ze6g3GBb7IdOGakZrTCZZmI5Q3ROXHOB6974a-4E5pfG5xfceFTtgxwkKSkNXSsaduSECqaRnUpCBbQti3USevTJtrY9tDJlAUvzJbo9onVa75yF7zKK1ZRnATebQS8-zVCiLzXQYIxwoIbp_8uUsXp1AN72Zt_0Idvt6FWIl1AW-VSXDmJ8kVZY1Y1lE7U_AEqPR2kIqbWVDrZtxzebzkkJsJlXIkxBL48Pfl_9vjnNvv2HrsGYeI6ODNOHRy2wfIGlN6F4EHdJRnnfJqs22zwabL4ZrKS26v7Bbpzuh2l4i8gFSJ0</recordid><startdate>20161011</startdate><enddate>20161011</enddate><creator>Jaikumkao, Krit</creator><creator>Pongchaidecha, Anchalee</creator><creator>Thongnak, La-Ongdao</creator><creator>Wanchai, Keerati</creator><creator>Arjinajarn, Phatchawan</creator><creator>Chatsudthipong, Varanuj</creator><creator>Chattipakorn, Nipon</creator><creator>Lungkaphin, Anusorn</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>IOV</scope><scope>ISR</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20161011</creationdate><title>Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity</title><author>Jaikumkao, Krit ; Pongchaidecha, Anchalee ; Thongnak, La-Ongdao ; Wanchai, Keerati ; Arjinajarn, Phatchawan ; Chatsudthipong, Varanuj ; Chattipakorn, Nipon ; Lungkaphin, Anusorn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c725t-8f53d3122dfb32aa810c4fe474298ea6a268de5c83887344a1b9f20406ff70cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aminoglycoside antibiotics</topic><topic>Aminoglycosides</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Antioxidants</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Atorvastatin</topic><topic>Atorvastatin Calcium - pharmacology</topic><topic>Atorvastatin Calcium - therapeutic use</topic><topic>Attenuation</topic><topic>Bcl-2 protein</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>Biology and Life Sciences</topic><topic>Blood Urea Nitrogen</topic><topic>Calpain</topic><topic>Caspase</topic><topic>Caspase 12 - metabolism</topic><topic>Caspase-12</topic><topic>Caspase-3</topic><topic>Cell cycle</topic><topic>Coenzyme A</topic><topic>Creatinine</topic><topic>Creatinine - blood</topic><topic>Cytokines</topic><topic>Diabetes</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Administration Schedule</topic><topic>Drug dosages</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>Fibrosis</topic><topic>Gangrene</topic><topic>Gentamicin</topic><topic>Gentamicins - toxicity</topic><topic>Health aspects</topic><topic>Heart failure</topic><topic>Heat-Shock Proteins - metabolism</topic><topic>Hydroxymethylglutaryl-CoA reductase</topic><topic>Hypertrophy</topic><topic>Inflammation</topic><topic>Injection</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - metabolism</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidneys</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Nephritis - chemically induced</topic><topic>Nephritis - pathology</topic><topic>Nephritis - prevention & control</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Nitric Oxide Synthase Type II - metabolism</topic><topic>Nitric-oxide synthase</topic><topic>Oxidative stress</topic><topic>Physiology</topic><topic>Protective Agents - pharmacology</topic><topic>Protective Agents - therapeutic use</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Renal function</topic><topic>Research and Analysis Methods</topic><topic>Rodents</topic><topic>Stress response</topic><topic>Transforming Growth Factor beta1 - metabolism</topic><topic>Transforming growth factor-b1</topic><topic>Transforming growth factors</topic><topic>Tumor necrosis factor-TNF</topic><topic>Urea</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jaikumkao, Krit</creatorcontrib><creatorcontrib>Pongchaidecha, Anchalee</creatorcontrib><creatorcontrib>Thongnak, La-Ongdao</creatorcontrib><creatorcontrib>Wanchai, Keerati</creatorcontrib><creatorcontrib>Arjinajarn, Phatchawan</creatorcontrib><creatorcontrib>Chatsudthipong, Varanuj</creatorcontrib><creatorcontrib>Chattipakorn, Nipon</creatorcontrib><creatorcontrib>Lungkaphin, Anusorn</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection (ProQuest)</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</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>Jaikumkao, Krit</au><au>Pongchaidecha, Anchalee</au><au>Thongnak, La-Ongdao</au><au>Wanchai, Keerati</au><au>Arjinajarn, Phatchawan</au><au>Chatsudthipong, Varanuj</au><au>Chattipakorn, Nipon</au><au>Lungkaphin, Anusorn</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-10-11</date><risdate>2016</risdate><volume>11</volume><issue>10</issue><spage>e0164528</spage><pages>e0164528-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27727327</pmid><doi>10.1371/journal.pone.0164528</doi><tpages>e0164528</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-10, Vol.11 (10), p.e0164528 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1827865144 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aminoglycoside antibiotics Aminoglycosides Animals Antibiotics Antioxidants Apoptosis Apoptosis - drug effects Atorvastatin Atorvastatin Calcium - pharmacology Atorvastatin Calcium - therapeutic use Attenuation Bcl-2 protein bcl-2-Associated X Protein - metabolism Biology and Life Sciences Blood Urea Nitrogen Calpain Caspase Caspase 12 - metabolism Caspase-12 Caspase-3 Cell cycle Coenzyme A Creatinine Creatinine - blood Cytokines Diabetes Dose-Response Relationship, Drug Drug Administration Schedule Drug dosages Endoplasmic reticulum Endoplasmic Reticulum Stress - drug effects Fibrosis Gangrene Gentamicin Gentamicins - toxicity Health aspects Heart failure Heat-Shock Proteins - metabolism Hydroxymethylglutaryl-CoA reductase Hypertrophy Inflammation Injection Interleukin 6 Interleukin-6 - metabolism Kidney - drug effects Kidney - metabolism Kidney - pathology Kidneys Laboratory animals Male Medicine Medicine and Health Sciences Nephritis - chemically induced Nephritis - pathology Nephritis - prevention & control NF-kappa B - metabolism NF-κB protein Nitric Oxide Synthase Type II - metabolism Nitric-oxide synthase Oxidative stress Physiology Protective Agents - pharmacology Protective Agents - therapeutic use Proteins Proto-Oncogene Proteins c-bcl-2 - metabolism Rats Rats, Sprague-Dawley Renal function Research and Analysis Methods Rodents Stress response Transforming Growth Factor beta1 - metabolism Transforming growth factor-b1 Transforming growth factors Tumor necrosis factor-TNF Urea |
| title | Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity |
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