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.

[1]  R. Schnellmann,et al.  Proteases in renal cell death: calpains mediate cell death produced by diverse toxicants. , 1998, Renal failure.

[2]  P. H. Bach,et al.  Adenine nucleotide and calpain inhibitor I protect against atractyloside-induced toxicity in rat renal cortical slices in vitro , 2001, Archives of Toxicology.

[3]  D. E. Goll,et al.  The calpain system. , 2003, Physiological reviews.

[4]  R. Schnellmann,et al.  The role of calpain in oncotic cell death. , 2004, Annual review of pharmacology and toxicology.

[5]  Afshin Samali,et al.  Mediators of endoplasmic reticulum stress‐induced apoptosis , 2006, EMBO reports.

[6]  J. Stevens,et al.  Modulating the endoplasmic reticulum stress response with trans-4,5-dihydroxy-1,2-dithiane prevents chemically induced renal injury in vivo. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[7]  H. Mehendale,et al.  Colchicine antimitosis causes progression of S-(1,2-dichlorovinyl)-L-cysteine-induced injury leading to acute renal failure and death in mice. , 2006, Toxicology.

[8]  M. Peyrou,et al.  Cisplatin, gentamicin, and p-aminophenol induce markers of endoplasmic reticulum stress in the rat kidneys. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[9]  Kartik Shankar,et al.  Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants. , 2003, Toxicology and applied pharmacology.

[10]  I. Calder,et al.  The nephrotoxicity of p-aminophenol. I. The effect on microsomal cytochromes, glutathione and covalent binding in kidney and liver. , 1979, Chemico-biological interactions.

[11]  G. Mudge,et al.  Nephrotoxicity of p-aminophenol, a metabolite of acetaminophen, in the fischer 344 rat. , 1982, Toxicology and applied pharmacology.

[12]  I. Calder,et al.  An experimental model of analgesic-induced renal damage--some effects of p-aminophenol on rat kidney mitochondria. , 1977, Xenobiotica; the fate of foreign compounds in biological systems.

[13]  Johan Hansson,et al.  Cisplatin Induces Endoplasmic Reticulum Stress and Nucleus-independent Apoptotic Signaling* , 2003, The Journal of Biological Chemistry.

[14]  M. Peyrou,et al.  Effect of endoplasmic reticulum stress preconditioning on cytotoxicity of clinically relevant nephrotoxins in renal cell lines. , 2007, Toxicology in vitro : an international journal published in association with BIBRA.

[15]  M. Peyrou,et al.  The Endoplasmic Reticulum in Xenobiotic Toxicity , 2005, Drug metabolism reviews.

[16]  E. Lunney,et al.  An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Davis,et al.  Early functional and morphological changes in renal tubular necrosis due to p-aminophenol. , 1983, Kidney international.

[18]  J. Hook,et al.  Acetaminophen and p-aminophenol nephrotoxicity in aging male Sprague-Dawley and Fischer 344 rats. , 1989, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[19]  S. Muruganandan,et al.  Calpain-induced endoplasmic reticulum stress and cell death following cytotoxic damage to renal cells. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[20]  L. Walker,et al.  FILTRATION FAILURE INDUCED BY pAMINOPHENOL IN RATS IS DUE TO RAISED INTRATUBULAR PRESSURE AND NOT CHANGES IN GLOMERULAR FUNCTION , 1990, Clinical and experimental pharmacology & physiology.

[21]  M. Valentovic,et al.  Time-dependent effect of p-aminophenol (PAP) toxicity in renal slices and development of oxidative stress. , 2005, Toxicology and applied pharmacology.

[22]  W. Dekant,et al.  p-aminophenol nephrotoxicity: biosynthesis of toxic glutathione conjugates. , 1992, Toxicology and applied pharmacology.

[23]  A. Sanz,et al.  J Am Soc Nephrol 15: 380–389, 2004 Paracetamol-Induced Renal Tubular Injury: A Role for ER Stress , 2022 .

[24]  E. Mazzon,et al.  Inhibitors of calpain activation (PD150606 and E-64) and renal ischemia-reperfusion injury. , 2005, Biochemical pharmacology.

[25]  J. Tarloff,et al.  Lack of correlation between para-aminophenol toxicity in vivo and in vitro in female Sprague-Dawley rats. , 1996, Fundamental and applied toxicology : official journal of the Society of Toxicology.