title: PJ34, a poly adenosine diphosphate-ribose polymerase inhibitor, attenuates chromate-induced nephrotoxicity.
abstract: Potassium dichromate (K(2)Cr(2)O(7))-induced nephrotoxicity is associated with oxidative stress. In addition, the activation of the polyadenosine diphosphate-ribose [poly(ADP-ribose)] polymerase-1 (PARP-1) plays a role in the pathophysiology of some diseases associated with oxidative stress. To clarify the potential role of PARP-1 in this experimental model, N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethyacetamide HCl (PJ34), a highly specific inhibitor of this enzyme, was used. Nephrotoxicity was induced in rats by a single sc injection of K(2)Cr(2)O(7); studies were performed 2 days later. PJ34 was given intraperitoneally (15 mg/kg) 1 hr before and 1, 5, 24, 26, 31 and 46 hr after K(2)Cr(2)O(7) injection. Nephrotoxicity was evaluated by histological analysis and by measuring blood urea nitrogen, serum creatinine, serum glutathione peroxidase activity and urinary excretion of N-acetyl-beta-D-glucosaminidase. PARP-1 activation was evaluated by the immunostaining of poly(ADP-ribose). In addition, the following markers of oxidative stress were evaluated: 3-nitrotyrosine, 4-hydroxy-2-nonenal, malondialdehyde and protein carbonyl content. K(2)Cr(2)O(7) increased poly(ADP-ribose) content suggesting the PARP-1 activation in this model. PJ34 significantly ameliorated the K(2)Cr(2)O(7)-induced: (i) nephrotoxicity, (ii) poly(ADP-ribose) accumulation and (iii) oxidative stress. It is concluded that PARP-1 is activated and involved, at least in part, in K(2)Cr(2)O(7)-induced nephrotoxicity in rats.
authors.affiliation: Department of Biology, School of Chemistry, National Autonomous University of Mexico, DF, Mexico.
authors.forename: Paola
authors.initials: P
authors.lastname: Yam-Canul
authors.forename: Yolanda Irasema
authors.initials: YI
authors.lastname: Chirino
authors.forename: Dolores Javier
authors.initials: DJ
authors.lastname: Sánchez-González
authors.forename: Claudia María
authors.initials: CM
authors.lastname: Martínez-Martínez
authors.forename: Cristino
authors.initials: C
authors.lastname: Cruz
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
mesh_terms: D000818:Animals; D005260:Female; D007274:Injections, Intraperitoneal; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011192:Potassium Dichromate / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D011192:Potassium Dichromate