Poly(ADP-ribose) polymerase-1 is a key mediator of cisplatin-induced kidney inflammation and injury

Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Free Radical Biology and Medicine (Impact Factor: 5.74). 08/2011; 51(9):1774-88. DOI: 10.1016/j.freeradbiomed.2011.08.006
Source: PubMed


Cisplatin is a commonly used chemotherapeutic drug, the clinical use of which is limited by the development of dose-dependent nephrotoxicity. Enhanced inflammatory response, oxidative stress, and cell death have been implicated in the development of cisplatin-induced nephropathy; however, the precise mechanisms are elusive. Overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) by oxidative DNA damage under various pathological conditions promotes cell death and up-regulation of key proinflammatory pathways. In this study, using a well-established model of nephropathy, we have explored the role of PARP-1 in cisplatin-induced kidney injury. Genetic deletion or pharmacological inhibition of PARP-1 markedly attenuated the cisplatin-induced histopathological damage, impaired renal function (elevated serum BUN and creatinine levels), and enhanced inflammatory response (leukocyte infiltration; TNF-α, IL-1β, F4/80, adhesion molecules ICAM-1/VCAM-1 expression) and consequent oxidative/nitrative stress (4-HNE, 8-OHdG, and nitrotyrosine content; NOX2/NOX4 expression). PARP inhibition also facilitated the cisplatin-induced death of cancer cells. Thus, PARP activation plays an important role in cisplatin-induced kidney injury, and its pharmacological inhibition may represent a promising approach to preventing the cisplatin-induced nephropathy. This is particularly exciting because several PARP inhibitors alone or in combination with DNA-damaging anticancer agents show considerable promise in clinical trials for treatment of various malignancies (e.g., triple-negative breast cancer).

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    • "In this context, PARP-1 inhibitors have been developed and widely used to potentiate the anti-tumor efficacy of a number of chemotherapeutic agents, including irradiation, temmolozolomide, irinotecan, and topotecan (Mégnin- Chanet et al., 2010). More importantly, PARP-1 inhibitors can also attenuate toxicities caused by chemotherapeutic agents, such as cisplatin nephrotoxicity and doxorubicin cardiomyotoxicity (Mukhopadhyay et al., 2011; Sarszegi et al., 2012; Wang et al., 2012b). Although the inhibition of DNA repair is generally considered as the key mechanism underlying PARP inhibitor-mediated chemosensitization (Wang et al., 2012b), it cannot explicate the chemodetoxification effect of PARP-1 inhibitors. "
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    • "Reactive oxygen species (ROS), which induce oxidative stress, are important in the pathogenesis of cisplatin-induced renal injury, and NAD(P)H oxidase 4 (NOX4) is one of the major sources of ROS generation in cisplatin-treated kidneys (Mukhopadhyay et al., 2010; 2011). Elevated levels of intracellular ROS lead to the oxidation of several cellular molecules, including proteins and lipids, resulting in cellular stress (Chen et al., 1995). "
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    • "The same group also reported the protective effect of FeTPPS, an iron based peroxynitrite scavenger, in a rat model of cisplatin toxicity [21]. Recently, mitochondrial antioxidants and downstream PARP inhibitors demonstrate protective effect against cisplatin toxicity in mice [22], [23]. "
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