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

Kidney Int. 2012 Jul;82(2):193-203. doi: 10.1038/ki.2012.64. Epub 2012 Mar 21.

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-κB, 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.

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / enzymology*
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control
  • Animals
  • Antineoplastic Agents*
  • Apoptosis
  • Cells, Cultured
  • Cisplatin*
  • Disease Models, Animal
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Inflammation Mediators / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Kidney Tubules / drug effects
  • Kidney Tubules / enzymology*
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Necrosis
  • Nephritis / chemically induced
  • Nephritis / enzymology*
  • Nephritis / genetics
  • Nephritis / pathology
  • Nephritis / prevention & control
  • Neutrophil Infiltration
  • Oxidative Stress
  • Phenanthrenes / pharmacology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / deficiency
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Signal Transduction
  • Time Factors
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Inflammation Mediators
  • N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
  • NF-kappa B
  • Phenanthrenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Cisplatin