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  • Title: Role of Bcl-xL in paracetamol-induced tubular epithelial cell death.
    Author: Lorz C, Justo P, Sanz AB, Egido J, Ortíz A.
    Journal: Kidney Int; 2005 Feb; 67(2):592-601. PubMed ID: 15673306.
    Abstract:
    BACKGROUND: Paracetamol overdose causes acute renal failure and chronic exposure to paracetamol has been linked to chronic renal failure. Recently, apoptosis induction has been identified as a possible mechanism of paracetamol nephrotoxicity. METHODS: Murine proximal tubular epithelial MCT cells were cultured in the presence of paracetamol. The effects of Bcl-xL overexpression, Bax antisense oligodeoxynucleotides, and different caspase inhibitors on cell death were studied. RESULTS: While paracetamol did not change the mRNA expression of the antiapoptotic gene bcl-xL, it decreased Bcl-xL protein levels. The decrease in Bcl-xL was prevented by lactacystin, but not by caspase inhibitors. Addition to the culture media of the survival factors present in fetal calf serum (FCS) increased Bcl-xL expression and decreased paracetamol-induced apoptosis. Overexpression of a human bcl-xL transgene decreased apoptosis induced by paracetamol by 60% at 24 hours and increased long-term cell survival. The constitutive expression of the viral caspase inhibitor CrmA decreased the rate of apoptosis by 60% at 24 hours and the broad-specific caspase inhibitor zVAD-fmk prevented paracetamol-induced features of apoptosis. However, caspase inhibitors did not prevent eventual cell death. Bax did not translocate to mitochondria and Bax antisense oligodeoxynucleotides were not protective. CONCLUSION: Our results suggest that induction of apoptosis may underlie the nephrotoxic potential of paracetamol and identify Bcl-xL as a player in toxic tubular cell injury.
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