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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway

Man Jiang1, Cong-Yi Wang, Shuang Huang

  • 1Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.

American Journal of Physiology. Renal Physiology
|March 13, 2009
PubMed

Insights

Cisplatin causes kidney damage through p53-independent pathways. This involves the mitochondrial apoptosis pathway, even without functional p53, highlighting new targets for preventing cisplatin nephrotoxicity.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cancer Therapy

Background:

  • Cisplatin is a vital chemotherapy drug, but its use is limited by kidney toxicity (nephrotoxicity).
  • The tumor suppressor protein p53 plays a role in cisplatin-induced kidney injury, but blocking it only partially protects the kidneys.
  • This suggests that p53-independent mechanisms contribute to cisplatin nephrotoxicity.

Purpose of the Study:

  • To investigate the p53-independent mechanisms of cisplatin-induced kidney cell apoptosis.
  • To elucidate the role of the mitochondrial pathway in cisplatin nephrotoxicity.

Main Methods:

  • Examined cisplatin-induced apoptosis in p53-deficient primary renal tubular cells and baby mouse kidney (BMK) cells.
  • Utilized caspase inhibitors, Bax/Bak knockout BMK cells, and Bcl-2 overexpression.
  • Assessed Bax activation, cytochrome c release, and apoptosis.

Main Results:

  • Cisplatin induced apoptosis in p53-deficient kidney cells via a caspase-dependent mitochondrial pathway.
  • Bax and Bak activation, mitochondrial translocation, and oligomerization were critical for cytochrome c release and apoptosis.
  • Inhibition of Bax/Bak or overexpression of Bcl-2 reduced cisplatin-induced apoptosis.

Conclusions:

  • A p53-independent mechanism contributes to cisplatin nephrotoxicity.
  • The mitochondrial apoptosis pathway, involving Bax and Bak, is a key player in this p53-independent injury.
  • Targeting the mitochondrial pathway may offer novel strategies for preventing cisplatin-induced kidney damage.

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