Key result
PARP1 inhibition protects human kidney cells from cisplatin-induced oxidative stress and necrosis via SIRT3 activation.
Why the study?
The mechanisms by which PARP1 inhibition protects against oxidative stress during cisplatin nephrotoxicity were not fully understood, particularly the role of SIRT3.
PARP1 inhibition protects kidney proximal tubular cells against cisplatin-induced oxidative stress and necrosis through SIRT3 activation.
May warrant preclinical testing in cisplatin nephrotoxicity models; leaves open any clinical role for PARP1 inhibition.
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.
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Yoon et al. (2016) studied Cisplatin nephrotoxicity. PJ34 hydrochloride (PARP1 inhibitor) vs. Cisplatin alone was evaluated on Oxidative stress and necrotic cell death. PARP1 inhibition with PJ34 hydrochloride protected human kidney proximal tubular cells against cisplatin-induced oxidative stress and necrotic cell death via SIRT3 activation.
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