title: Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury.
abstract: Clinical prescription of cisplatin, one of the most widely used chemotherapeutic agents, is limited by its side effects, particularly tubular injury-associated nephrotoxicity. Since details of the underlying mechanisms are not fully understood, we investigated the role of pyruvate dehydrogenase kinase (PDK) in cisplatin-induced acute kidney injury. Among the PDK isoforms, PDK4 mRNA and protein levels were markedly increased in the kidneys of mice treated with cisplatin, and c-Jun N-terminal kinase activation was involved in cisplatin-induced renal PDK4 expression. Treatment with the PDK inhibitor sodium dichloroacetate (DCA) or genetic knockout of PDK4 attenuated the signs of cisplatin-induced acute kidney injury, including apoptotic morphology of the kidney tubules along with numbers of TUNEL-positive cells, cleaved caspase-3, and renal tubular injury markers. Cisplatin-induced suppression of the mitochondrial membrane potential, oxygen consumption rate, expression of electron transport chain components, cytochrome c oxidase activity, and disruption of mitochondrial morphology were noticeably improved in the kidneys of DCA-treated or PDK4 knockout mice. Additionally, levels of the oxidative stress marker 4-hydroxynonenal and mitochondrial reactive oxygen species were attenuated, whereas superoxide dismutase 2 and catalase expression and glutathione synthetase and glutathione levels were recovered in DCA-treated or PDK4 knockout mice. Interestingly, lipid accumulation was considerably attenuated in DCA-treated or PDK4 knockout mice via recovered expression of peroxisome proliferator-activated receptor-α and coactivator PGC-1α, which was accompanied by recovery of mitochondrial biogenesis. Thus, PDK4 mediates cisplatin-induced acute kidney injury, suggesting that PDK4 might be a therapeutic target for attenuating cisplatin-induced acute kidney injury.
authors.affiliation: Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Chae-Myeong
authors.initials: CM
authors.lastname: Ha
authors.affiliation: Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.affiliation: Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea.
authors.forename: Sungmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea.
authors.forename: Mi Sun
authors.initials: MS
authors.lastname: Choe
authors.affiliation: Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Daegu, Gyeongbuk, Republic of Korea.
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
authors.affiliation: Nano-Bio Electron Microscopy Research Group, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Yang Hoon
authors.initials: YH
authors.lastname: Huh
authors.affiliation: Nano-Bio Electron Microscopy Research Group, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Nano-Bio Electron Microscopy Research Group, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Hee-Seok
authors.initials: HS
authors.lastname: Kweon
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Sun Joo
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Jae-Han
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Roudebush VA Medical Center and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: kpark@knu.ac.kr.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea; Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: leei@knu.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002945:Cisplatin; D004195:Disease Models, Animal; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002945:Cisplatin
keywords: cisplatin; fatty acid oxidation; kidney injury; mitochondrial dysfunction; pyruvate dehydrogenase kinase 4; reactive oxygen species