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

Research output: Contribution to journalArticle

27 Citations (Scopus)

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

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F2-Isoprostanes
Cisplatin
Cysteine
Kidney
Wounds and Injuries
Isoprostanes
Sulfhydryl Compounds
Lipid Peroxidation
Glutathione
Chlorides
Vasoconstriction
L-Lactate Dehydrogenase
Arachidonic Acid
Epithelial Cells
Ions

ASJC Scopus subject areas

  • Nephrology

Cite this

Cisplatin induces N-acetyl cysteine suppressible F2 isoprostane production and injury in renal tubular epithehal cells. / Salahudeen, Abdulla; Poovala, Vandana; Parry, Wilson; Pande, Ravi; Kanji, Vijaya; Ansari, Naseem; Morrow, Jason; Roberts, Jackson.

In: Journal of the American Society of Nephrology, Vol. 9, No. 8, 08.1998, p. 1448-1455.

Research output: Contribution to journalArticle

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, vol. 9, no. 8, pp. 1448-1455.
Salahudeen, Abdulla ; Poovala, Vandana ; Parry, Wilson ; Pande, Ravi ; Kanji, Vijaya ; Ansari, Naseem ; Morrow, Jason ; Roberts, Jackson. / Cisplatin induces N-acetyl cysteine suppressible F2 isoprostane production and injury in renal tubular epithehal cells. In: Journal of the American Society of Nephrology. 1998 ; Vol. 9, No. 8. pp. 1448-1455.
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