Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
Department of Anesthesiology, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
Am J Physiol Renal Physiol. 2020 Dec 1;319(6):F1073-F1080. doi: 10.1152/ajprenal.00354.2020. Epub 2020 Oct 26.
Cisplatin, a commonly used anticancer drug, has been shown to induce acute kidney injury, which limits its clinical use in cancer treatment. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is activated by various cellular stresses that deplete cellular ATP. However, the potential role of AMPK in cisplatin-induced apoptosis of renal tubular epithelial cells has not been studied. In this study, we demonstrated that cisplatin activates AMPK (Thr phosphorylation) in cultured renal tubular epithelial cells in a time-dependent manner, which was associated with p53 phosphorylation. Compound C, a selective AMPK inhibitor, suppressed cisplatin-induced AMPK activation, p53 phosphorylation, Bax induction, and caspase 3 activation. Furthermore, silencing AMPK expression by siRNA attenuated cisplatin-induced p53 phosphorylation, Bax induction, and caspase 3 activation. In a mouse model of cisplatin-induced kidney injury, compound C inhibited p53 phosphorylation, Bax expression, caspase 3 activation, and apoptosis, protecting the kidney from injury and dysfunction. Taken together, these results suggest that the AMPK-p53-Bax signaling pathway plays a crucial role in cisplatin-induced tubular epithelial cell apoptosis.
顺铂是一种常用的抗癌药物，已被证明会导致急性肾损伤，这限制了其在癌症治疗中的临床应用。新出现的证据表明，AMP 激活的蛋白激酶（AMPK）作为细胞能量传感器，可被各种消耗细胞 ATP 的细胞应激激活。然而，AMPK 在顺铂诱导的肾小管上皮细胞凋亡中的潜在作用尚未得到研究。在这项研究中，我们证明顺铂以时间依赖的方式在培养的肾小管上皮细胞中激活 AMPK（Thr 磷酸化），这与 p53 磷酸化有关。选择性 AMPK 抑制剂化合物 C 抑制顺铂诱导的 AMPK 激活、p53 磷酸化、Bax 诱导和 caspase 3 激活。此外，siRNA 沉默 AMPK 表达可减弱顺铂诱导的 p53 磷酸化、Bax 诱导和 caspase 3 激活。在顺铂诱导的肾损伤小鼠模型中，化合物 C 抑制 p53 磷酸化、Bax 表达、caspase 3 激活和细胞凋亡，从而保护肾脏免受损伤和功能障碍。总之，这些结果表明，AMPK-p53-Bax 信号通路在顺铂诱导的管状上皮细胞凋亡中起关键作用。
