Document Detail


The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity.
MedLine Citation:
PMID:  19144690     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Navjotsingh Pabla; Robert F Murphy; Kebin Liu; Zheng Dong
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-01-14
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  296     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2009 Mar 
Date Detail:
Created Date:  2009-02-23     Completed Date:  2009-05-06     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F505-11     Citation Subset:  IM    
Affiliation:
Department of Cellular Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912, USA.
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MeSH Terms
Descriptor/Qualifier:
Acute Kidney Injury / chemically induced*
Animals
Antineoplastic Agents / metabolism*,  poisoning
Apoptosis / drug effects
Cation Transport Proteins / metabolism*
Cell Line
Cimetidine / pharmacology
Cisplatin / metabolism*,  poisoning
Humans
Kidney Tubules / metabolism*
Mice
Mice, Inbred C57BL
Necrosis / metabolism
Organic Cation Transport Proteins / antagonists & inhibitors
RNA Interference
Rats
Grant Support
ID/Acronym/Agency:
R01 CA133085/CA/NCI NIH HHS; R01 CA133085-02/CA/NCI NIH HHS; R01 CA133085-04/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cation Transport Proteins; 0/Ctr1 protein, mouse; 0/Organic Cation Transport Proteins; 0/Slc22a2 protein, mouse; 15663-27-1/Cisplatin; 51481-61-9/Cimetidine
Comments/Corrections

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