title: The effect of poly (ADP-ribose) polymerase inhibition on aminoglycoside-induced acute tubular necrosis in rats.
abstract: BACKGROUND
  Aminoglycosides (AG) cause nephrotoxicity in 10 - 20% of patients. One of the mechanisms is by generating reactive oxygen species (ROS), leading to DNA destruction and activation of poly(ADPribose) polymerase (PARP) causing necrotic tubular cell death. PARP inhibition on gentamicin-induced nephrotoxicity was studied.
  
  
  METHODS
  19 female Wistar-Kyoto rats divided into 3 groups: control (3 rats receiving no treatment); gentamicin-treated group (8 rats); and 8 rats treated with gentamicin combined with 3-aminobenzamide (3 AB). Kidney functions, protein, and gentamicin levels as well as urinary trypsin inhibitory activity (TIA) were measured. Tissue microscopic examination and immunohistochemical study for proliferative cell nuclear antigen (PCNA) were determined. The effect of PARP inhibitor on the bactericidal activity of gentamicin was also assessed.
  
  
  RESULTS
  The following results were statistically significant: urea (mg/dL) 39.9 ± 5.86, 88.3 ± 50.3, and 48.5 ± 12.7 (p = 0.048); serum creatinine (mg/dL): 0.6 ± 0.26, 1.05 ± 0.7, 0.6 ± 0.06 (p = 0.043); proteinuria (mg/24-hours): 7.27 ± 3.65, 41.2 ± 18.1, and 17.6 ± 13.9 (p = 0.050); the number of tubular macronuclei (per 10 mm2): 18.33 ± 16.07, 218 ± 101.8, 41.7 ± 36.2 (p = 0.012); the number of dilated tubes (per 10 mm2): 61.67 ± 12.58, 276.3 ± 112.7, 140.0 ± 90.9 (p = 0.04); and the number of PCNA positive nuclei (per 10 mm2): 223.3 ± 95.69, 3,585 ± 2,215.3, 626.7 ± 236.9 (p = 0.034) in the control, gentamicin, and gentamicin+3AB-treated groups, respectively. The following biochemical and histologic parameters were also examined, however, they showed no statistically significant difference: TIA (p = 0.055), mitoses (p = 0.14), mononuclear infiltrate (p = 0.188), and intratubular cast formation (p = 0.084). No effect on bactericidal activity was observed.
  
  
  CONCLUSIONS
  This study illustrates that PARP inhibitor significantly attenuates gentamicin-induced nephrotoxicity in rats with no effect on the bactericidal activity.
authors.forename: Alexander
authors.initials: A
authors.lastname: Biro
authors.forename: Hananya
authors.initials: H
authors.lastname: Vaknine
authors.forename: Malka
authors.initials: M
authors.lastname: Cohen-Armon
authors.forename: Zipora
authors.initials: Z
authors.lastname: Matas
authors.forename: Asora
authors.initials: A
authors.lastname: Fux
authors.forename: Letizia
authors.initials: L
authors.lastname: Schreiber
authors.forename: Esther
authors.initials: E
authors.lastname: Berger
authors.forename: Michael
authors.initials: M
authors.lastname: Dan
authors.forename: Mona
authors.initials: M
authors.lastname: Boaz
authors.forename: Olga
authors.initials: O
authors.lastname: Gregoriev
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Katzir
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001549:Benzamides / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D004108:Dilatation, Pathologic / Q000473:pathology; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects; D005260:Female; D005839:Gentamicins / Q000009:adverse effects* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011500:Protein Synthesis Inhibitors / Q000009:adverse effects*; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000009:adverse effects; D014361:Trypsin Inhibitors / Q000652:urine; D014508:Urea / Q000097:blood
chemical_list: D000900:Anti-Bacterial Agents; D001549:Benzamides; D005839:Gentamicins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; D014361:Trypsin Inhibitors; C025160:3-aminobenzamide; D014508:Urea; D003404:Creatinine; D011065:Poly(ADP-ribose) Polymerases