Cisplatin induces N-acetyl cysteine suppressible F2 isoprostane production and injury in renal tubular epithehal cells

Abdulla Salahudeen, Vandana Poovala, Wilson Parry, Ravi Pande, Vijaya Kanji, Naseem Ansari, Jason Morrow, Jackson Roberts

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    27 Scopus citations

    Abstract

    In the low intracellular chloride milieu, chloride ions of cisplatin may exchange for cellular SH moieties resulting in glutathione depletion, H2O2 accumulation, and lipid peroxidation. Cisplatin-induced lipid peroxidation, in addition to causing direct cellular injury, may further contribute to cisplatininduced renal dysfunction by generating vasoconstrictive E2-and F2-isoprostanes. The aim of this study was to determine whether cisplatin- induced renal epithelial (LLC-PK1 and primary human proximal tubular) cell injury is associated with increased production of isoprostanes, and whether this can be suppressed with a thiol donor, N-acetyl cysteine. It was confirmed that incubation of renal epithelial cells with cisplatin resulted in N-acetyl cysteine-inhibitable glutathione depletion, H2O2 accumulation, lipid degradation, and lactate dehydroge- nase release. In additional experiments, incubation of cells with cisplatin for 48 h was accompanied by a dose-related increase in total (free plus esterified) F2-isoprostanes. An increase in F2-isoprostanes was discernible at 16.5 μM cisplatin and doubled at 66.0 μM. N-Acetyl cysteine at 50 μM concentration effectively suppressed 66.0 μM cisplatin-induced increase in isoprostanes. Similar findings were also obtained in human cells. Thus, cisplatin-induced tubular cell injury is accompanied by increased isoprostane production through a mechanism involving thiol depletion. On the basis of this new finding, it is hypothesized that these arachidonic acid peroxidation products may be partially responsible for the cisplatin-induced renal vasoconstriction demonstrable in the in vivo models.

    Original languageEnglish (US)
    Pages (from-to)1448-1455
    Number of pages8
    JournalJournal of the American Society of Nephrology
    Volume9
    Issue number8
    StatePublished - Aug 1998

    ASJC Scopus subject areas

    • Nephrology

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  • Cite this

    Salahudeen, A., Poovala, V., Parry, W., Pande, R., Kanji, V., Ansari, N., Morrow, J., & Roberts, J. (1998). Cisplatin induces N-acetyl cysteine suppressible F2 isoprostane production and injury in renal tubular epithehal cells. Journal of the American Society of Nephrology, 9(8), 1448-1455.