Pabla Navjotsingh, Murphy Robert F, Liu Kebin, Dong Zheng
Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912, USA.
Am J Physiol Renal Physiol. 2009 Mar;296(3):F505-11. doi: 10.1152/ajprenal.90545.2008. Epub 2009 Jan 14.
The usefulness and efficacy of cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of cisplatin nephrotoxicity, much less is known about the mechanism of cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake. Consistently, downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake. Notably, cimetidine can further reduce cisplatin uptake and cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity.
顺铂是一种化疗药物，其有效性和功效受到其对包括肾脏在内的正常组织和器官毒性的限制。顺铂在肾小管细胞中的摄取量很高，导致顺铂积累以及肾小管细胞损伤和死亡，最终引发急性肾衰竭。尽管广泛的研究集中在顺铂肾毒性的信号通路，但对于肾细胞和组织摄取顺铂的机制了解甚少。在这方面，已有证据表明有机阳离子转运体（OCT），特别是OCT2参与其中。铜转运体Ctr1在肾小管细胞中高度表达；然而，其在顺铂肾毒性中的作用尚不清楚。在本研究中，我们证明Ctr1主要在小鼠肾脏的近端和远端肾小管细胞中表达。我们进一步表明，Ctr1主要定位于这些细胞的基底外侧，这是一个推测的顺铂摄取位点。重要的是，通过小干扰RNA或铜预处理下调Ctr1会导致顺铂摄取减少。一致地，下调Ctr1可抑制顺铂毒性，包括通过凋亡和坏死导致的细胞死亡。西咪替丁是OCT2的一种药理抑制剂，也可部分减弱顺铂摄取。值得注意的是，西咪替丁可进一步降低Ctr1下调细胞中的顺铂摄取和顺铂毒性。这些结果首次证明了Ctr1在顺铂摄取和肾毒性中的作用。
