title: Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity.
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.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA.
authors.forename: Jinu
authors.initials: J
authors.lastname: Kim
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Long
authors.forename: Kang
authors.initials: K
authors.lastname: Tang
authors.forename: Babu J
authors.initials: BJ
authors.lastname: Padanilam
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis; D002478:Cells, Cultured; D002945:Cisplatin; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009393:Nephritis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D020556:Neutrophil Infiltration; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D016328:NF-kappa B; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin