Anat Cell Biol.  2015 Mar;48(1):66-74. 10.5115/acb.2015.48.1.66.

Cisplatin induces primary necrosis through poly(ADP-ribose) polymerase 1 activation in kidney proximal tubular cells

• Park S
• Yoon SP
• Kim J

• KMID: 2046077
• DOI: http://doi.org/10.5115/acb.2015.48.1.66

Abstract

Treatment with cisplatin for cancer therapy has a major side effect such as nephrotoxicity; however, the role of poly (ADP-ribose) polymerase 1 (PARP1) in necrosis in response to cisplatin nephrotoxicity remains to be defined. Here we report that cisplatin induces primary necrosis through PARP1 activation in kidney proximal tubular cells derived from human, pig and mouse. Treatment with high dose of cisplatin for 4 and 8 hours induced primary necrosis, as represented by the percentage of propidium iodide-positive cells and lactate dehydrogenase release. The primary necrosis was correlated with PARP1 activation during cisplatin injury. Treatment with PJ34, a potent PARP1 inhibitor, at 2 hours after injury attenuated primary necrosis after 8 hours of cisplatin injury as well as PARP1 activation. PARP1 inhibition also reduced the release of lactate dehydrogenase and high mobility group box protein 1 from kidney proximal tubular cells at 8 hours after cisplatin injury. Oxidative stress was increased by treatment with cisplatin for 8 hours as shown by 8-hydroxy-2'-deoxyguanosine and lipid hydroperoxide assays, but PARP1 inhibition at 2 hours after injury reduced the oxidative damage. These data demonstrate that cisplatin-induced PARP1 activation contributes to primary necrosis through oxidative stress in kidney proximal tubular cells, resulting in the induction of cisplatin nephrotoxicity and inflammation.

Keyword

Cisplatin; Nephrotoxicity; Necrosis; Poly(ADP-ribose) polymerase 1; Kidney proximal tubular cell

MeSH Terms

Animals
Cisplatin*
Humans
Inflammation
Kidney*
L-Lactate Dehydrogenase
Lipid Peroxides
Mice
Necrosis*
Oxidative Stress
Poly(ADP-ribose) Polymerases*
Propidium
Cisplatin
L-Lactate Dehydrogenase
Lipid Peroxides
Poly(ADP-ribose) Polymerases
Propidium