title: Poly(ADP-ribose) polymerase-1 is a key mediator of cisplatin-induced kidney inflammation and injury.
abstract: 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).
authors: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Partha
authors: P
authors: Mukhopadhyay
authors: Béla
authors: B
authors: Horváth
authors: Malek
authors: M
authors: Kechrid
authors: Galin
authors: G
authors: Tanchian
authors: Mohanraj
authors: M
authors: Rajesh
authors: Amarjit S
authors: AS
authors: Naura
authors: A Hamid
authors: AH
authors: Boulares
authors: Pál
authors: P
authors: Pacher
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000378:metabolism*
chemical_list: C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin