Paracetamol-induced renal tubular injury: a role for ER stress.
Paracetamol (also known as acetaminophen) causes acute and chronic renal failure. While the mechanisms leading to hepatic injury have been extensively studied, the molecular mechanisms of paracetamol-induced nephrotoxicity are poorly defined. Paracetamol induced cell death with features of apoptosis in murine proximal tubular epithelial cells. While paracetamol increased the expression of the death receptor Fas on the cell surface, the Fas pathway was not involved in the paracetamol-induced apoptosis of tubular cells. The mitochondrial pathway was not activated during paracetamol-induced apoptosis; there was no dissipation of mitochondrial potential or release of apoptogenic factors such as cytochrome c or Smac/DIABLO. However, paracetamol-induced apoptosis is a caspase-dependent process that involves activation of caspase-9 and caspase-3 in the absence of cytosolic cytochrome c or Smac/DIABLO. The authors also detected induction of endoplasmic reticulum (ER) stress, characterized by GADD153 upregulation and translocation to the nucleus, as well as caspase-12 cleavage. Interestingly, after treatment of murine tubular cells with paracetamol and calpain inhibitors, the caspase-12 cleavage product was still detectable, and calpain inhibitors were unable to protect tubular cells from paracetamol-induced apoptosis. The results suggest that induction of apoptosis may underlie the nephrotoxic potential of paracetamol and identify ER stress as a therapeutic target in nephrotoxicity.
Lorz
Corina
C
Laboratory of Experimental Nephrology and Vascular Pathology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
Justo
Pilar
P
Sanz
Ana
A
Subirá
Dolores
D
Egido
Jesús
J
Ortiz
Alberto
A
D000082:Acetaminophen / Q000009:adverse effects*; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12; D020169:Caspases / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000473:pathology; D051379:Mice; D014415:Tunicamycin / Q000494:pharmacology; D019014:fas Receptor / Q000187:drug effects
D018712:Analgesics, Non-Narcotic; D019014:fas Receptor; D014415:Tunicamycin; D000082:Acetaminophen; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases