ToxSci Advance Access published online on June 12, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm152
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Cisplatin, Gentamicin, and p-Aminophenol Induce Markers of Endoplasmic Reticulum Stress in the Rat Kidneys
* Biomedical Sciences, University of Prince Edward Island, Charlottetown, PE, C1A4P3, CANADA, mpeyrou{at}upei.ca and acribb{at}upei.ca
Pathology and Microbiology, University of Prince Edward Island, Charlottetown, PE, C1A 4P3, CANADA, hanna{at}upei.ca
Corresponding Author: Dr Mathieu Peyrou, Biomedical Sciences, University of Prince Edward Island, 550 University Av., Charlottetown, PE C1A 4P3, Canada, Phone: +1 902 566 0802, Fax: +1 902 566 0832, mpeyrou{at}upei.ca
Received December 6, 2006; revision received May 11, 2007; accepted June 6, 2007
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Abstract |
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In vitro evidence of the involvement of the endoplasmic reticulum (ER) during drug-induced renal toxicity is accumulating. ER stress and ER-mediated cell death markers have been reported after exposure of renal cells to model toxicants and nephrotoxic drugs in various in vitro models, but in vivo experiments with clinically-relevant nephrotoxic compounds are lacking. In order to determine the relevance of the in vitro findings, markers of ER stress (XBP1 mRNA processing and protein expression; GRP78 and GRP94 upregulation) and ER-mediated cell death (caspase-12 and calpain activation) were examined in kidney tissue of rats exposed to nephrotoxic doses of cisplatin, gentamicin and p-aminophenol, a nephrotoxic metabolite of acetaminophen. XBP1 signalling was observed with all three drugs and was associated with increased expression of GRP94 and GRP78 in gentamicin and p-aminophenol treated animals, but surprisingly not after cisplatin exposure. m-calpain expression was increased after 7 days of cisplatin treatment, whereas it was decreased in p-aminophenol treated rats. Caspase-12 cleavage products were increased after cisplatin, gentamicin and p-aminophenol administration. The results of this study demonstrate that three clinically relevant nephrotoxic drugs are all associated with changes in markers of ER stress and ER-mediated cell death in vivo. Further investigation is warranted to determine the role of the ER, the calpain system and caspase-12 in drug-induced renal cell death.
Key Words: Endoplasmic reticulum stress; nephrotoxicity; nephrotoxic drugs; caspase; calpain.
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