Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
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.
Kidney Int. 2017 Apr;91(4):880-895. doi: 10.1016/j.kint.2016.10.011. Epub 2016 Dec 28.
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.
顺铂是最广泛使用的化疗药物之一，其临床处方受到其副作用的限制，特别是肾小管损伤相关的肾毒性。由于其潜在机制的细节尚未完全了解，我们研究了丙酮酸脱氢酶激酶 (PDK) 在顺铂诱导的急性肾损伤中的作用。在 PDK 同工酶中，顺铂处理的小鼠肾脏中 PDK4 mRNA 和蛋白水平明显增加，c-Jun N 端激酶激活参与了顺铂诱导的肾脏 PDK4 表达。用 PDK 抑制剂二氯乙酸钠 (DCA) 治疗或 PDK4 基因敲除可减轻顺铂诱导的急性肾损伤的迹象，包括肾小管的凋亡形态以及 TUNEL 阳性细胞、裂解的 caspase-3 和肾小管损伤标志物的数量。顺铂诱导的线粒体膜电位抑制、耗氧量、电子传递链成分的表达、细胞色素 c 氧化酶活性以及线粒体形态的破坏在 DCA 治疗或 PDK4 敲除小鼠的肾脏中明显改善。此外，氧化应激标志物 4-羟基壬烯醛和线粒体活性氧的水平降低，而超氧化物歧化酶 2 和过氧化氢酶的表达以及谷胱甘肽合酶和谷胱甘肽水平在 DCA 治疗或 PDK4 敲除小鼠中恢复。有趣的是，通过恢复过氧化物酶体增殖物激活受体-α和共激活因子 PGC-1α 的表达，脂滴积累在 DCA 治疗或 PDK4 敲除小鼠中明显减少，这伴随着线粒体生物发生的恢复。因此，PDK4 介导顺铂诱导的急性肾损伤，表明 PDK4 可能是减轻顺铂诱导的急性肾损伤的治疗靶点。
