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ToxSci Advance Access published online on June 12, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm105
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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

Calpain Inhibition but Not Reticulum Endoplasmic Stress Preconditioning Protects Rat Kidneys from p-Aminophenol Toxicity

Mathieu Peyrou, DVM, MSc*

Paul E. Hanna, DVM, MSc{dagger}

Alastair E. Cribb, DVM, PhD*

* Biomedical Sciences, University of Prince Edward Island, Charlottetown, PE, CANADA {dagger} Pathology and Microbiology, University of Prince Edward Island, Charlottetown, PE, CANADA

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 February 10, 2007; revision received April 9, 2007; accepted April 29, 2007


  Abstract

p-Aminophenol (pAP, 225 mg/kg) administration to rats induced renal failure and has been associated with markers of endoplasmic reticulum (ER) stress, as well as calpain and caspase-12 activation in kidneys. To determine the importance of ER stress and calpain during pAP-induced nephrotoxicity, rats were pre-treated with low, non-toxic, doses of ER stress inducers or with the selective calpain inhibitor PD150606 (3 mg/kg). Prior ER stress induced by tunicamycin and oxidized dithiothreitol did not result in protection against renal failure, but PD150606 administration was protective and decreased significantly the rise in creatinine and blood urea nitrogen observed after 24 hours post pAP administration. pAP-induced XBP1 upregulation was not modified by calpain inhibition, but a trend to lower GRP94 induction was determined, suggesting that pAP-induced ER stress was mostly calpain-independent. In contrast, pAP-induced caspase-12 cleavage products were significantly decreased with PD150606 pre-treatment, demonstrating that caspase-12 activation was calpain dependent. This study reveals the importance of calpain in pAP-induced renal failure. Further research with other nephrotoxicants needs to be performed to determine if calpain activation is a common feature of drug-induced renal failure.

Key Words: p-Aminophenol; XBP1; Calpain; Caspase-12; Nephrotoxicity; Endoplasmic reticulum stress.


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