Anat Cell Biol.  2016 Sep;49(3):165-176. 10.5115/acb.2016.49.3.165.

Poly(ADP-ribose) polymerase 1 contributes to oxidative stress through downregulation of sirtuin 3 during cisplatin nephrotoxicity

• Yoon SP
• Kim J

• KMID: 2353341
• DOI: http://doi.org/10.5115/acb.2016.49.3.165

Abstract

Enhanced oxidative stress is a hallmark of cisplatin nephrotoxicity, and inhibition of poly(ADP-ribose) polymerase 1 (PARP1) attenuates oxidative stress during cisplatin nephrotoxicity; however, the precise mechanisms behind its action remain elusive. Here, using an in vitro model of cisplatin-induced injury to human kidney proximal tubular cells, we demonstrated that the protective effect of PARP1 inhibition on oxidative stress is associated with sirtuin 3 (SIRT3) activation. Exposure to 400 µM cisplatin for 8 hours in cells decreased activity and expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPX), and SIRT3, while it increased their lysine acetylation. However, treatment with 1 µM PJ34 hydrochloride, a potent PARP1 inhibitor, restored activity and/or expression in those antioxidant enzymes, decreased lysine acetylation of those enzymes, and improved SIRT3 expression and activity in the cisplatin-injured cells. Using transfection with SIRT3 double nickase plasmids, SIRT3-deficient cells given cisplatin did not show the ameliorable effect of PARP1 inhibition on lysine acetylation and activity of antioxidant enzymes, including MnSOD, catalase and GPX. Furthermore, SIRT3 deficiency in cisplatin-injured cells prevented PARP1 inhibition-induced increase in forkhead box O3a transcriptional activity, and upregulation of MnSOD and catalase. Finally, loss of SIRT3 in cisplatin-exposed cells removed the protective effect of PARP1 inhibition against oxidative stress, represented by the concentration of lipid hydroperoxide and 8-hydroxy-2'-deoxyguanosine; and necrotic cell death represented by a percentage of propidium iodide-positively stained cells. Taken together, these results indicate that PARP1 inhibition protects kidney proximal tubular cells against oxidative stress through SIRT3 activation during cisplatin nephrotoxicity.

Keyword

Poly(ADP-ribose) polymerases; Sirtuin 3; Cisplatin; Nephrotoxicity; Oxidative stress; Manganese superoxide dismutase; Catalase; Glutathione peroxidase; Lysine acetylation

MeSH Terms

Acetylation
Catalase
Cell Death
Cisplatin*
Deoxyribonuclease I
Down-Regulation*
Glutathione Peroxidase
Humans
In Vitro Techniques
Kidney
Lipid Peroxides
Lysine
Oxidative Stress*
Plasmids
Poly Adenosine Diphosphate Ribose*
Poly(ADP-ribose) Polymerases*
Propidium
Sirtuin 3*
Superoxide Dismutase
Transfection
Up-Regulation
Catalase
Cisplatin
Deoxyribonuclease I
Glutathione Peroxidase
Lipid Peroxides
Lysine
Poly Adenosine Diphosphate Ribose
Poly(ADP-ribose) Polymerases
Propidium
Sirtuin 3
Superoxide Dismutase