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Updated: Aug 13, 2026

Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
15:43

Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes

Published on: January 7, 2013

Cisplatin-induced renal cell apoptosis: caspase 3-dependent and -independent pathways

Brian S Cummings1, Rick G Schnellmann

  • 1Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, Charleston, SC 29425, USA.

The Journal of Pharmacology and Experimental Therapeutics
|June 18, 2002
PubMed

Insights

Cisplatin induces kidney cell death (apoptosis) partly through the p53 protein, independent of mitochondrial damage or caspases 8/9. This p53 pathway activates caspase 3, but another 50% of cisplatin-induced apoptosis occurs independently.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Toxicology

Background:

  • Cisplatin is a widely used chemotherapeutic agent.
  • Cisplatin is known to cause nephrotoxicity, leading to renal proximal tubular cell (RPTC) apoptosis.
  • The precise molecular mechanisms underlying cisplatin-induced RPTC apoptosis are not fully elucidated.

Purpose of the Study:

  • To investigate the roles of p53, caspases 3, 8, and 9, and mitochondria in cisplatin-induced RPTC apoptosis.
  • To determine the signaling pathways involved in cisplatin-induced cell death.

Main Methods:

  • RPTCs were treated with cisplatin (50 microM).
  • Apoptosis markers including caspase activity, phosphatidylserine externalization, chromatin condensation, and DNA hypoploidy were measured.
  • Mitochondrial membrane potential and ATP levels were assessed.
  • The expression of nuclear p53 was analyzed.
  • Inhibitors of p53 (PFT), caspase 3 (DEVD-fmk), and broad-spectrum caspases (ZVAD-fmk) were used to probe signaling pathways.

Main Results:

  • Cisplatin induced time-dependent apoptosis in RPTCs, characterized by cell shrinkage, increased caspase 3 activity, phosphatidylserine externalization, chromatin condensation, and DNA hypoploidy.
  • Mitochondrial function (membrane potential, ATP levels) and caspase 8/9 activities remained unchanged.
  • Nuclear p53 expression increased preceding caspase 3 activation and chromatin condensation.
  • Inhibition of p53 partially blocked cisplatin-induced apoptosis markers.
  • Inhibition of caspase 3 or broad-spectrum caspases partially blocked apoptosis markers but did not affect p53 nuclear expression.

Conclusions:

  • At least 50% of cisplatin-induced RPTC apoptosis is mediated by p53, which activates caspase 3 independently of caspase 8/9 or mitochondrial dysfunction.
  • The remaining 50% of cisplatin-induced RPTC apoptosis occurs independently of p53 and the caspases 3, 8, and 9 signaling pathways.
  • These findings highlight a complex, multi-faceted mechanism of cisplatin-induced nephrotoxicity.

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