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Kidney Slices of Human and Rat to Characterize Cisplatin-Induced Injury on Cellular Pathways and Morphology

Preclinical Safety, Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, New Jersey 07936, USA, vickers_alison{at}allergan.com

Kristine Rose

Preclinical Safety, Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, New Jersey 07936, USA

Robyn Fisher

Vitron, Inc., Tucson, Arizona, USA

Muriel Saulnier

Preclinical Safety, Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, New Jersey 07936, USA

Pritam Sahota

Preclinical Safety, Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, New Jersey 07936, USA

Philip Bentley

Preclinical Safety, Novartis Pharmaceuticals Corporation, One Health Plaza, E. Hanover, New Jersey 07936, USA

Kidney slices represent an in vitro model that has the cellular complexity of in vivo tissue to provide insights into mechanisms of organ injury, as shown in this study with the model nephrotoxicant cisplatin. Cell pathways altered by cisplatin exposure are assessed by gene expression analysis, cell function, and morphology in human and rat kidney slices in comparison to rat kidney from an in vivo study. The acute nephrosis of the tubular epithelium induced by cisplatin in vivo was reproduced in both human and rat kidney slices, while the glomerulus appeared resistant even at high concentrations. Kidney gene expression changes of in vivo and in vitro samples were indicative of transcription, DNA damage, cell cycle, proliferation, and apoptosis that are in agreement with the mechanism of cisplatin causing DNA damage, growth arrest, and apoptosis; while genes indicative of protein damage, the disruption of transport and calcium homeostasis, cellular metabolism, and oxidative stress are pathways linked with cisplatin binding to various cellular proteins and macromolecules. Both concentration and time-dependent gene expression changes evident in the in vitro model preceded a change in tissue morphology. Functional assays confirming cell dysfunction and increased apoptosis revealed the rat kidney to be more sensitive to the effects of cisplatin than human kidney as demonstrated by significant decreases in slice ATP and GSH levels, significant increases in caspase 9 and 3 activity, p53 protein levels, and increased DNA laddering. The regional markers of proximal and distal tubular injury, alpha- and pi-glutathione S-transferases, were shown for the human kidney slices to be significantly increased by cisplatin. In this study, cisplatin-induced nephrotoxicity was demonstrated morphologically in rat and human kidney slices, and the associated gene expression and functional changes characterized the cellular pathways involved.

Key Words: Cisplatin injury • kidney slices • rat and human.

Toxicologic Pathology, Vol. 32, No. 5, 577-590 (2004)
DOI: 10.1080/01926230490508821


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