Calpain inhibition but not reticulum endoplasmic stress preconditioning protects rat kidneys from p-aminophenol toxicity.
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 pretreated with low, nontoxic, 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-h 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 pretreatment, 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.
Peyrou
Mathieu
M
Biomedical Sciences, University of Prince Edward Island, Charlottetown, PE, Canada. mpeyrou@upei.ca
Hanna
Paul E
PE
Cribb
Alastair E
AE
D000179:Acrylates / Q000494:pharmacology; D000627:Aminophenols / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053454:Caspase 12 / Q000096:biosynthesis; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D014415:Tunicamycin / Q000494:pharmacology
D000179:Acrylates; D000627:Aminophenols; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009153:Mutagens; C100442:PD 150606; D014415:Tunicamycin; D003404:Creatinine; D002154:Calpain; C506443:Casp12 protein, rat; D053454:Caspase 12; C026729:4-aminophenol; D004229:Dithiothreitol