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

• Published in: Free radical biology & medicine 2011-11, Vol.51 (9), p.1774-1788
• Main Authors: Mukhopadhyay, Partha, Horváth, Béla, Kechrid, Malek, Tanchian, Galin, Rajesh, Mohanraj, Naura, Amarjit S., Boulares, A. Hamid, Pacher, Pál
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; adhesion; Animals; blood serum; breast neoplasms; cell death; chemotherapy; Cisplatin; Cisplatin - toxicity; clinical trials; creatinine; death; DNA damage; Free radicals; histopathology; inflammation; Inflammation - chemically induced; Inflammation - metabolism; interleukin-1beta; kidney diseases; kidneys; leukocytes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephropathy; nephrotoxicity; oxidative stress; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - deficiency; Poly(ADP-ribose) Polymerases - metabolism; renal function; tumor necrosis factor-alpha
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2011.08.006

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). [Display omitted] ► Cisplatin is an important chemotherapeutic drug that causes nephrotoxicity/nephropathy ► The nephrotoxicity of cisplatin involves oxidative/nitrative stress-PARP pathway ► PARP-1 deletion/inhibition prevents cisplatin-induced kindey inflammation and injury ► PARP inhibition enhances the antitumor effect of cisplatin in human cancer(s)/cells ► PARP is a novel therapeutic target to prevent cisplatin's nephrotoxicity