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

Chang Joo Oh, Chae Myeong Ha, Young Keun Choi, Sungmi Park, Mi Sun Choe, Nam Ho Jeoung, Yang Hoon Huh, Hyo Jeong Kim, Hee Seok Kweon, Ji min Lee, Sun Joo Lee, Jae Han Jeon, Robert Harris, Keun Gyu Park, In Kyu Lee

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
JournalKidney International
DOIs
StateAccepted/In press - Feb 2 2016

Keywords

  • Cisplatin
  • Fatty acid oxidation
  • Kidney injury
  • Mitochondrial dysfunction
  • Pyruvate dehydrogenase kinase 4
  • Reactive oxygen species

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology

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    Oh, C. J., Ha, C. M., Choi, Y. K., Park, S., Choe, M. S., Jeoung, N. H., Huh, Y. H., Kim, H. J., Kweon, H. S., Lee, J. M., Lee, S. J., Jeon, J. H., Harris, R., Park, K. G., & Lee, I. K. (Accepted/In press). Pyruvate dehydrogenase kinase 4 deficiency attenuates cisplatin-induced acute kidney injury. Kidney International. https://doi.org/10.1016/j.kint.2016.10.011