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

Partha Mukhopadhyay, Béla Horváth, Malek Kechrid, Galin Tanchian, Mohanraj Rajesh, Amarjit S. Naura, A. Hamid Boulares, Pál Pacher

Research output: Contribution to journalArticlepeer-review

71 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)1774-1788
Number of pages15
JournalFree Radical Biology and Medicine
Volume51
Issue number9
DOIs
Publication statusPublished - Nov 1 2011
Externally publishedYes

Keywords

  • Cisplatin
  • Free radicals
  • Nephropathy
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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