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

Identification: Oh, Chang Joo


Description

Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury
 
Chang Joo Oh1, Gwon-Soo Jung1, Yun-A Jung1, Mi-Jin Kim1, Jun-Kyu Byun2, Hui-Jeon Jeon3, Seokmin Jeong2, SeungHyeong Lee2, Mihayng Park2, Gilwon Kang2, Jin-Hak Jung3, Myungsu Jung3, Yeon-Kyung Choi1, Keun-Gyu Park1,2,3, In-Kyu Lee1,2,3
1Department of Internal Medicine and Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, South Korea; 2Department of Biomedical Science and Department of pharmacy, Graduate School, Kyungpook National University; BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, South Korea; 3Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea
 
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. 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. 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, catalase, 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.
 

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