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Paracetamol-Induced Renal Tubular Injury: A Role for ER Stress

Corina Lorz^*, Pilar Justo^*, Ana Sanz^*, Dolores Subirá, Jesús Egido^* and Alberto Ortiz^*

*Laboratory of Experimental Nephrology and Vascular Pathology, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain; and Unidad de Hematología, Fundación Jiménez Díaz, Madrid, Spain.

Correspondence to: Alberto Ortiz, Laboratorio de Nefrología Experimental y Patología Vascular, Fundación Jiménez Díaz, Av Reyes Católicos 2l, 28040 Madrid, Spain. Phone: 34-915504940; Fax: 34-915494764; E-mail: aortiz{at}fjd.es

ABSTRACT. 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673