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Cisplatin nephrotoxicity is mediated by deoxyribonuclease I

Alexei G Basnakian1, Eugene O Apostolov, Xiaoyan Yin

  • 1University of Arkansas for Medical Sciences, Department of Internal Medicine, Division of Nephrology, 4301 W. Markham Street #501, Little Rock, AR 72205, USA. basnakianalexeig@uams.edu

Journal of the American Society of Nephrology : JASN
|January 14, 2005
PubMed

Insights

Deoxyribonuclease I (DNase I) plays a key role in cisplatin-induced kidney damage. DNase I knockout mice show significant protection against this chemotherapy-related nephrotoxicity.

Area of Science:

  • Nephrology
  • Oncology
  • Molecular Biology

Background:

  • Cisplatin is a vital chemotherapy drug, but its use is restricted by kidney toxicity (nephrotoxicity).
  • The precise mechanism of cisplatin-induced nephrotoxicity remains unclear but involves DNA fragmentation by an unknown endonuclease.
  • Deoxyribonuclease I (DNase I) is a known active renal endonuclease, and its inhibition protects kidney cells in vitro.

Purpose of the Study:

  • To investigate the specific role of deoxyribonuclease I (DNase I) in cisplatin-induced nephrotoxicity.
  • To determine if DNase I is the endonuclease responsible for cisplatin-induced kidney damage.

Main Methods:

  • Utilized deoxyribonuclease I (DNase I) knockout (KO) mice and primary renal tubular epithelial cells from these mice.
  • Assessed cisplatin toxicity in vitro using cultured renal tubular epithelial cells.
  • Evaluated cisplatin-induced nephrotoxicity in vivo using functional (blood urea nitrogen, serum creatinine) and histological (tubular necrosis, DNA fragmentation) markers in DNase I KO mice.

Main Results:

  • DNase I accounts for approximately 80% of renal endonuclease activity.
  • Renal tubular epithelial cells from DNase I KO mice were resistant to cisplatin injury in vitro.
  • DNase I KO mice exhibited significant protection against cisplatin-induced nephrotoxicity, with improved functional and histological outcomes.

Conclusions:

  • Deoxyribonuclease I (DNase I) is essential for the development of cisplatin-induced nephrotoxicity.
  • Targeting DNase I may offer a protective strategy against chemotherapy-induced kidney damage.

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