Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity

Jinu Kim, Kelly E. Long, Kang Tang, Babu J Padanilam

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Apoptosis, necrosis, and inflammation are hallmarks of cisplatin nephrotoxicity; however, the role and mechanisms of necrosis and inflammation remains undefined. As poly(ADP-ribose) polymerase 1 (PARP1) inhibition or its gene deletion is renoprotective in several renal disease models, we tested whether its activation may be involved in cisplatin nephrotoxicity. Parp1 deficiency was found to reduce cisplatin-induced kidney dysfunction, oxidative stress, and tubular necrosis, but not apoptosis. Moreover, neutrophil infiltration, activation of nuclear factor-B, c-Jun N-terminal kinases, p38 mitogen-activated protein kinase, and upregulation of proinflammatory genes were all abrogated by Parp1 deficiency. Using proximal tubule epithelial cells isolated from Parp1-deficient and wild-type mice and pharmacological inhibitors, we found evidence for a PARP1/Toll-like receptor 4/p38/tumor necrosis factor-α axis following cisplatin injury. Furthermore, pharmacological inhibition of PARP1 protected against cisplatin-induced kidney structural/functional damage and inflammation. Thus, our findings suggest that PARP1 activation is a primary signal and its inhibition/loss protects against cisplatin-induced nephrotoxicity. Targeting PARP1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity.

Original languageEnglish (US)
Pages (from-to)193-203
Number of pages11
JournalKidney International
Volume82
Issue number2
DOIs
StatePublished - Jul 2 2012

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Cisplatin
Necrosis
Inflammation
Kidney
Pharmacology
Apoptosis
Neutrophil Activation
Toll-Like Receptor 4
Neutrophil Infiltration
JNK Mitogen-Activated Protein Kinases
Gene Deletion
p38 Mitogen-Activated Protein Kinases
Poly (ADP-Ribose) Polymerase-1
Oxidative Stress
Up-Regulation
Tumor Necrosis Factor-alpha
Epithelial Cells
Wounds and Injuries
Genes

ASJC Scopus subject areas

  • Nephrology

Cite this

Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity. / Kim, Jinu; Long, Kelly E.; Tang, Kang; Padanilam, Babu J.

In: Kidney International, Vol. 82, No. 2, 02.07.2012, p. 193-203.

Research output: Contribution to journalArticle

Kim, Jinu ; Long, Kelly E. ; Tang, Kang ; Padanilam, Babu J. / Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity. In: Kidney International. 2012 ; Vol. 82, No. 2. pp. 193-203.
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