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ToxSci Advance Access published online on February 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi117
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received December 6, 2004
Accepted February 10, 2005

Systems Toxicology

Cisplatin-induced apoptosis is enhanced by hypoxia and by inhibition of mitochondria in renal collecting duct cells

Gerald Schwerdt 1*, Ruth Freudinger 1, Claudia Schuster 1, Florian Weber 1, Oliver Thews 1, and Michael Gekle 1

1 Physiologisches Institut, Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany

* To whom correspondence should be addressed.
Gerald Schwerdt, E-mail: gerald.schwerdt{at}mail.uni-wuerzburg.de


  Abstract

Cisplatin is a widely used chemotherapeutic agent. Here we show that cisplatin induces apoptosis in renal collecting duct-derived cells (MDCK-C7 cells, resembling principal cells) in a dose-dependent manner. Additionally, we studied the role of mitochondria in this process by inhibition of the mitochondrial respiratory chain, the F1Fo-ATP synthase or by uncoupling. The role of intra- and extracellular pH in apoptosis induction was investigated. Activation of caspase-3 and DNA ladder formation were used to monitor the apoptotic response. When cells were incubated with inhibitors of the mitochondrial respiratory chain or an inhibitor of the ATP-synthase, cisplatin- induced apoptosis was markedly enhanced. Mitochondrial blockade led to enhanced production of lactic acid. Also, anoxia potentiated the cisplatininduced caspase-3 activation. Neither intra- nor extracellular pH had an influence on caspase- 3 activation at low cisplatin concentrations. Acidic conditions (pH 6.8) potentiated the caspase-3 activation when high (100 µM) cisplatin concentrations were used. We demonstrate that intact mitochondria are important to prevent cisplatin-induced apoptosis in MDCK-C7 cells and that acidic conditions can aggravate the toxic effects of cisplatin.

Keywords: cisplatin; hypoxia; collecting duct; apoptosis; mitochondria.
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