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Kidney Int. 2017 Apr;91(4):880-895. doi: 10.1016/j.kint.2016.10.011. Epub 2016 Dec 28.

Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury.

Author information

1
Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
2
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.
3
Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Republic of Korea.
4
Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea.
5
Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Daegu, Gyeongbuk, Republic of Korea.
6
Nano-Bio Electron Microscopy Research Group, Korea Basic Science Institute, Daejeon, Republic of Korea.
7
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
8
Roudebush VA Medical Center and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
9
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: kpark@knu.ac.kr.
10
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.

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.

KEYWORDS:

cisplatin; fatty acid oxidation; kidney injury; mitochondrial dysfunction; pyruvate dehydrogenase kinase 4; reactive oxygen species

PMID:
28040265
DOI:
10.1016/j.kint.2016.10.011
[Indexed for MEDLINE]

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