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.
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.
Wainford
Richard David
RD
Department of Medicine and Therapeutics, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. rwainf@lsuhsc.edu
Weaver
Richard J
RJ
Hawksworth
Gabrielle M
GM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity*; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D015415:Biomarkers; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C034697:transplatin; D016190:Carboplatin; D002945:Cisplatin