The immediate early genes, c-fos, c-jun and AP-1, are early markers of platinum analogue toxicity in human proximal tubular cell primary cultures

Richard David Wainford, Richard J Weaver, Gabrielle M Hawksworth

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Abstract

These studies tested the hypothesis that c-fos, c-jun and AP-1 are early markers of platinum analogue-induced proximal tubule nephrotoxicity in primary rat proximal tubule (RPT) and human proximal tubule (HPT) cell cultures. The order of platinum analogue toxicity was cisplatin > transplatin > carboplatin in RPT and HPT cultures. Following a 2-h platinum analogue treatment, c-fos protein expression correlated with toxicity. Maximal c-fos protein levels were observed at 8-h (RPT) and 4-h (HPT) post-platinum analogue treatment. c-jun and AP-1 protein levels were maximal 4-h and 8-h, respectively, post cisplatin treatment in HPT cultures. In contrast, c-jun and AP-1 protein were not detected in RPT cultures. c-fos and c-jun mRNA levels were maximal at 60 and 120-min in RPT cell cultures, respectively, whilst c-fos and c-jun mRNA levels were maximal at 120-min in HPT cultures. Differences between HPT and RPT responses to cisplatin reveal inter-species differences associated with induction of c-fos and c-jun mRNA and protein, which in turn form the functional AP-1 complex prior to the onset of cellular toxicity. These studies highlight the utility of HPT cultures as an invitro model system, and the potential of c-fos and c-jun as early markers of nephrotoxicity to screen therapeutic lead compounds.
Original languageEnglish
Pages (from-to)780-788
Number of pages9
JournalToxicology in Vitro
Volume23
Issue number5
Early online date19 Apr 2009
DOIs
Publication statusPublished - Aug 2009

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Keywords

  • early markers of toxicity
  • rat and human proximal tubular cell cultures
  • platinum analogues
  • c-fos
  • c-jun
  • AP-1

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