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ToxSci Advance Access originally published online on June 12, 2007
Toxicological Sciences 2007 99(1):346-353; doi:10.1093/toxsci/kfm152
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cisplatin, Gentamicin, and p-Aminophenol Induce Markers of Endoplasmic Reticulum Stress in the Rat Kidneys

Mathieu Peyrou*,1, Paul E. Hanna{dagger} and Alastair E. Cribb*

* Biomedical Sciences {dagger} Pathology and Microbiology, University of Prince Edward Island, Charlottetown, PE, C1A 4P3 Canada

1 To whom correspondence should be addressed at Biomedical Sciences, University of Prince Edward Island, 550 University Av., Charlottetown, PE C1A 4P3 Canada. Fax: (902) 566-0832. E-mail: mpeyrou{at}upei.ca.

Received December 6, 2006; accepted June 6, 2007


  Abstract

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 messenger RNA 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 (CIS), gentamicin (GEN), and p-aminophenol (PAP), a nephrotoxic metabolite of acetaminophen. XBP1 signaling was observed with all three drugs and was associated with increased expression of GRP94 and GRP78 in GEN- and PAP-treated animals, but surprisingly not after CIS exposure. m-Calpain expression was increased after 7 days of CIS treatment, whereas it was decreased in PAP-treated rats. Caspase-12 cleavage products were increased after CIS, GEN, and PAP 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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