title: The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity.
abstract: 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.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912, USA.
authors.forename: Navjotsingh
authors.initials: N
authors.lastname: Pabla
authors.forename: Robert F
authors.initials: RF
authors.lastname: Murphy
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000506:poisoning; D017209:Apoptosis / Q000187:drug effects; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism* / Q000506:poisoning; D000079923:Copper Transporter 1; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors; D000075102:Organic Cation Transporter 2; D034622:RNA Interference; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491012:Slc22a2 protein, mouse; C490077:Slc31a1 protein, mouse; D002927:Cimetidine; D002945:Cisplatin