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1 Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veteran Healthcare System, Little Rock, AR, USA
2 Department of Internal Medicine and Therapeutics, Osaka University, Osaka, Japan
* To whom correspondence should be addressed. E-mail: iarany{at}uams.edu.
Cisplatin treatment induces extensive death of the proximal tubules in mice. We have also demonstrated that treatment of immortalized mouse proximal tubule cells (TKPTS) with 25 µM cisplatin induces apoptotic death in vitro. Here we demonstrate that members of the mitogen activated protein kinases (MAPKs) such as the extracellular signal regulated kinase (ERK), the c-jun N-terminal kinase (JNK) and the p38 are all activated after cisplatin treatment both in vivo and in vitro. Since MAPKs mediate cell survival and death, we studied their role in cisplatin-induced cell death in vitro. Apoptosis was confirmed by cell morphology, fluorescence-activated cell sorting (FACS) analysis, annexin V/propidium iodide binding and caspase-3 activation in TKPTS cells. Inhibition of ERK, but not JNK or p38, abolished caspase-3 activation and apoptotic death, suggesting a pro-death role of ERK in CP-induced injury. We also determined that CP-induced ERK as well as caspase-3 activation is epidermal growth factor receptor (EGFR) - and c-src-dependent since inhibition of these genes inhibited ERK and caspase-3 activation and attenuated apoptotic death. These results suggest that caspase-3 mediates cisplatin-induced cell death in TKPTS cells via an EGFR/src/ERK-dependent pathway. We also suggest that the pro-death effect of ERK is injury type-dependent since during oxidant injury ERK supports survival rather than death in the same cells. We propose that injury-specific outcome diverges downstream from ERK in cisplatin or H2O2 mediated cell survival and death.
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