PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis
Abstract Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome p...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-05-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.14078 |
| _version_ | 1818994569447997440 |
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| author | Takuma Iwaki Brock G. Bennion Erin K. Stenson Jared C. Lynn Cynthia Otinga Danijel Djukovic Daniel Raftery Lin Fei Hector R. Wong W. Conrad Liles Stephen W. Standage |
| author_facet | Takuma Iwaki Brock G. Bennion Erin K. Stenson Jared C. Lynn Cynthia Otinga Danijel Djukovic Daniel Raftery Lin Fei Hector R. Wong W. Conrad Liles Stephen W. Standage |
| author_sort | Takuma Iwaki |
| collection | DOAJ |
| description | Abstract Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation. |
| first_indexed | 2024-12-20T21:00:02Z |
| format | Article |
| id | doaj.art-8526c3b7b2e94040ac04c4a89bde337d |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-12-20T21:00:02Z |
| publishDate | 2019-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-8526c3b7b2e94040ac04c4a89bde337d2022-12-21T19:26:43ZengWileyPhysiological Reports2051-817X2019-05-01710n/an/a10.14814/phy2.14078PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsisTakuma Iwaki0Brock G. Bennion1Erin K. Stenson2Jared C. Lynn3Cynthia Otinga4Danijel Djukovic5Daniel Raftery6Lin Fei7Hector R. Wong8W. Conrad Liles9Stephen W. Standage10Department of Pediatrics University of Washington School of Medicine Seattle WashingtonDepartment of Pediatrics University of Washington School of Medicine Seattle WashingtonDepartment of Pediatrics Section of Critical Care University of Colorado School of Medicine Anschutz Medical Center Children's Hospital Colorado Aurora ColoradoDepartment of Pediatrics University of Washington School of Medicine Seattle WashingtonDepartment of Pediatrics University of Washington School of Medicine Seattle WashingtonDepartment of Chemistry and Biochemistry University of Colorado Boulder ColoradoDepartment of Anesthesiology and Pain Medicine University of Washington School of Medicine Seattle WashingtonDivision of Biostatistics and Epidemiology Cincinnati Children's Hospital Medical Center Cincinnati OhioDivision of Critical Care Medicine Cincinnati Children's Hospital Medical Center Cincinnati OhioDepartment of Medicine University of Washington School of Medicine Seattle WashingtonDepartment of Pediatrics University of Washington School of Medicine Seattle WashingtonAbstract Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation.https://doi.org/10.14814/phy2.14078Acute kidney injurylipid metabolismperoxisome proliferator‐activated receptor alphasepsis |
| spellingShingle | Takuma Iwaki Brock G. Bennion Erin K. Stenson Jared C. Lynn Cynthia Otinga Danijel Djukovic Daniel Raftery Lin Fei Hector R. Wong W. Conrad Liles Stephen W. Standage PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis Physiological Reports Acute kidney injury lipid metabolism peroxisome proliferator‐activated receptor alpha sepsis |
| title | PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis |
| title_full | PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis |
| title_fullStr | PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis |
| title_full_unstemmed | PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis |
| title_short | PPARα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis |
| title_sort | pparα contributes to protection against metabolic and inflammatory derangements associated with acute kidney injury in experimental sepsis |
| topic | Acute kidney injury lipid metabolism peroxisome proliferator‐activated receptor alpha sepsis |
| url | https://doi.org/10.14814/phy2.14078 |
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