Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity
Objective This study aimed to investigate the potential protective effect of sitagliptin on gentamicin‐induced nephrotoxicity and to elucidate the underlying mechanism. Methods Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin...
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| Veröffentlicht in: | Journal of pharmacy and pharmacology 2016-04, Vol.68 (4), p.523-532 |
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| creator | Abuelezz, Sally A. Hendawy, Nevien Abdel Gawad, Sara |
| description | Objective
This study aimed to investigate the potential protective effect of sitagliptin on gentamicin‐induced nephrotoxicity and to elucidate the underlying mechanism.
Methods
Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and Control group: received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase‐3 and bax were evaluated.
Key findings
Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase‐3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment.
Conclusion
These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney. |
| doi_str_mv | 10.1111/jphp.12534 |
| format | Article |
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This study aimed to investigate the potential protective effect of sitagliptin on gentamicin‐induced nephrotoxicity and to elucidate the underlying mechanism.
Methods
Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and Control group: received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase‐3 and bax were evaluated.
Key findings
Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase‐3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment.
Conclusion
These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney.</description><identifier>ISSN: 0022-3573</identifier><identifier>EISSN: 2042-7158</identifier><identifier>DOI: 10.1111/jphp.12534</identifier><identifier>PMID: 27019059</identifier><identifier>CODEN: JPPMAB</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; Antioxidants - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Apoptosis Regulatory Proteins - metabolism ; Biomarkers - blood ; Blood Glucose - drug effects ; Blood Glucose - metabolism ; Blood Urea Nitrogen ; Creatinine - blood ; Cytoprotection ; Dehydrogenases ; Disease Models, Animal ; Electron Transport - drug effects ; Energy Metabolism - drug effects ; gentamicin ; Gentamicins ; Kidney - drug effects ; Kidney - metabolism ; Kidney - pathology ; Kidney Diseases - chemically induced ; Kidney Diseases - metabolism ; Kidney Diseases - pathology ; Kidney Diseases - prevention & control ; Lipid Peroxidation - drug effects ; Male ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondria - pathology ; Mitochondrial DNA ; mitochondrial dysfunction ; nephrotoxicity ; Oxidative stress ; Oxidative Stress - drug effects ; Proteinuria - chemically induced ; Proteinuria - metabolism ; Proteinuria - prevention & control ; Rats, Wistar ; Rodents ; sitagliptin ; Sitagliptin Phosphate - pharmacology ; Urine</subject><ispartof>Journal of pharmacy and pharmacology, 2016-04, Vol.68 (4), p.523-532</ispartof><rights>2016 Royal Pharmaceutical Society</rights><rights>2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.</rights><rights>Copyright © 2016 Royal Pharmaceutical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4284-83d0c1d8732ffd414ffb76f16977c354a2805b0f16e2c3eac30b1f4b0649382f3</citedby><cites>FETCH-LOGICAL-c4284-83d0c1d8732ffd414ffb76f16977c354a2805b0f16e2c3eac30b1f4b0649382f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjphp.12534$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjphp.12534$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27019059$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abuelezz, Sally A.</creatorcontrib><creatorcontrib>Hendawy, Nevien</creatorcontrib><creatorcontrib>Abdel Gawad, Sara</creatorcontrib><title>Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity</title><title>Journal of pharmacy and pharmacology</title><addtitle>J Pharm Pharmacol</addtitle><description>Objective
This study aimed to investigate the potential protective effect of sitagliptin on gentamicin‐induced nephrotoxicity and to elucidate the underlying mechanism.
Methods
Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and Control group: received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase‐3 and bax were evaluated.
Key findings
Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase‐3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment.
Conclusion
These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>Antioxidants - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Biomarkers - blood</subject><subject>Blood Glucose - drug effects</subject><subject>Blood Glucose - metabolism</subject><subject>Blood Urea Nitrogen</subject><subject>Creatinine - blood</subject><subject>Cytoprotection</subject><subject>Dehydrogenases</subject><subject>Disease Models, Animal</subject><subject>Electron Transport - drug effects</subject><subject>Energy Metabolism - drug effects</subject><subject>gentamicin</subject><subject>Gentamicins</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidney Diseases - chemically induced</subject><subject>Kidney Diseases - metabolism</subject><subject>Kidney Diseases - pathology</subject><subject>Kidney Diseases - prevention & control</subject><subject>Lipid Peroxidation - drug effects</subject><subject>Male</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial DNA</subject><subject>mitochondrial dysfunction</subject><subject>nephrotoxicity</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Proteinuria - chemically induced</subject><subject>Proteinuria - metabolism</subject><subject>Proteinuria - prevention & control</subject><subject>Rats, Wistar</subject><subject>Rodents</subject><subject>sitagliptin</subject><subject>Sitagliptin Phosphate - pharmacology</subject><subject>Urine</subject><issn>0022-3573</issn><issn>2042-7158</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhSMEokNhwwMgS2xQpRT_JHGyrCqYARWYRRHsLMe-7nhI7GA7becteGQ8nbYLFlxZutdX3zmyfIriNcGnJNf77bSZTgmtWfWkWFBc0ZKTun1aLDCmtGQ1Z0fFixi3GGPeNM3z4ohyTDpcd4viz9kwwLWVyXqHvEEBnBzQaJNXG-90sPmmd9HMTt0h0mkkJz8lH21Es9MQBgsRpQ2gKfgEGbsGBMbkaW8YbZJXg52SdSifK3BJjlZZV1qnZwUaOZg2Welv8zbtXhbPjBwivLrvx8X3jx8uz1flxbflp_Ozi1JVtK3KlmmsiG45o8boilTG9LwxpOk4V6yuJG1x3eO8AKoYSMVwT0zV46bqWEsNOy7eHXzzq3_PEJMYbVQwDNKBn6MgWV9jRgjO6Nt_0K2fQ_6nTPG2wpi1jGXq5ECp4GMMYMQU7CjDThAs9jmJfU7iLqcMv7m3nPsR9CP6EEwGyAG4sQPs_mMlPq9X6wfT8qCxMcHto0aGX6LhjNfix9el-PJzdcnWdSeW7C-UUq_4</recordid><startdate>201604</startdate><enddate>201604</enddate><creator>Abuelezz, Sally A.</creator><creator>Hendawy, Nevien</creator><creator>Abdel Gawad, Sara</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>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>201604</creationdate><title>Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity</title><author>Abuelezz, Sally A. ; Hendawy, Nevien ; Abdel Gawad, Sara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4284-83d0c1d8732ffd414ffb76f16977c354a2805b0f16e2c3eac30b1f4b0649382f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Animals</topic><topic>Antioxidants - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Biomarkers - blood</topic><topic>Blood Glucose - drug effects</topic><topic>Blood Glucose - metabolism</topic><topic>Blood Urea Nitrogen</topic><topic>Creatinine - blood</topic><topic>Cytoprotection</topic><topic>Dehydrogenases</topic><topic>Disease Models, Animal</topic><topic>Electron Transport - drug effects</topic><topic>Energy Metabolism - drug effects</topic><topic>gentamicin</topic><topic>Gentamicins</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidney Diseases - chemically induced</topic><topic>Kidney Diseases - metabolism</topic><topic>Kidney Diseases - pathology</topic><topic>Kidney Diseases - prevention & control</topic><topic>Lipid Peroxidation - drug effects</topic><topic>Male</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - pathology</topic><topic>Mitochondrial DNA</topic><topic>mitochondrial dysfunction</topic><topic>nephrotoxicity</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Proteinuria - chemically induced</topic><topic>Proteinuria - metabolism</topic><topic>Proteinuria - prevention & control</topic><topic>Rats, Wistar</topic><topic>Rodents</topic><topic>sitagliptin</topic><topic>Sitagliptin Phosphate - pharmacology</topic><topic>Urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Abuelezz, Sally A.</creatorcontrib><creatorcontrib>Hendawy, Nevien</creatorcontrib><creatorcontrib>Abdel Gawad, Sara</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Journal of pharmacy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Abuelezz, Sally A.</au><au>Hendawy, Nevien</au><au>Abdel Gawad, Sara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity</atitle><jtitle>Journal of pharmacy and pharmacology</jtitle><addtitle>J Pharm Pharmacol</addtitle><date>2016-04</date><risdate>2016</risdate><volume>68</volume><issue>4</issue><spage>523</spage><epage>532</epage><pages>523-532</pages><issn>0022-3573</issn><eissn>2042-7158</eissn><coden>JPPMAB</coden><abstract>Objective
This study aimed to investigate the potential protective effect of sitagliptin on gentamicin‐induced nephrotoxicity and to elucidate the underlying mechanism.
Methods
Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and Control group: received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase‐3 and bax were evaluated.
Key findings
Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase‐3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment.
Conclusion
These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>27019059</pmid><doi>10.1111/jphp.12534</doi><tpages>10</tpages></addata></record> |
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| source | MEDLINE; Wiley Journals; Oxford University Press Journals All Titles (1996-Current) |
| subjects | Adenosine Triphosphate - metabolism Animals Antioxidants - pharmacology Apoptosis Apoptosis - drug effects Apoptosis Regulatory Proteins - metabolism Biomarkers - blood Blood Glucose - drug effects Blood Glucose - metabolism Blood Urea Nitrogen Creatinine - blood Cytoprotection Dehydrogenases Disease Models, Animal Electron Transport - drug effects Energy Metabolism - drug effects gentamicin Gentamicins Kidney - drug effects Kidney - metabolism Kidney - pathology Kidney Diseases - chemically induced Kidney Diseases - metabolism Kidney Diseases - pathology Kidney Diseases - prevention & control Lipid Peroxidation - drug effects Male Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Mitochondrial DNA mitochondrial dysfunction nephrotoxicity Oxidative stress Oxidative Stress - drug effects Proteinuria - chemically induced Proteinuria - metabolism Proteinuria - prevention & control Rats, Wistar Rodents sitagliptin Sitagliptin Phosphate - pharmacology Urine |
| title | Alleviation of renal mitochondrial dysfunction and apoptosis underlies the protective effect of sitagliptin in gentamicin-induced nephrotoxicity |
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