Role of the poly(ADP-ribose)polymerase activity in vancomycin-induced renal injury.
The aim of the present study was to investigate the role of poly(ADP-ribose)polymerase (PARP) activity in vancomycin (VCM)-induced renal injury and to determine whether 1,5-isoquinelinediol (ISO), a PARP inhibitor agent, could be offered as an alternative therapy in VCM-induced renal impairment. Rats were divided into four groups as follows: (i) control (Group 1); (ii) VCM-treated (Group 2); (iii) VCM plus ISO-treated (Group 3); and (iv) ISO-treated (Group 4). VCM (200mg/kg, i.p., twice daily) was administered to Groups 2 and 3 for 7 days. ISO (3mg/kg/day, i.p.) treatment was started 24h before the first administration of VCM and continued for 8 days. After the 14th VCM injection, the animals were placed in metabolic cages to collect urine samples. All the rats were sacrificed by decapitation, blood samples were taken in tubes and kidneys were excised immediately. Blood urea nitrogen (BUN) and plasma creatinine, and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) were used as markers of VCM-induced renal injury in rats. Light microscopy was used to evaluate semi-quantitative analysis of the kidney sections. Poly(ADP-ribose) (PAR, the product of activated PARP) and PARP-1 expressions in renal tissues were demonstrated by immunohistochemistry and Western blot. VCM administration increased BUN levels from 8.07+/-0.75 mg/dL to 53.87+/-10.11 mg/dL. The plasma creatinine levels were 0.8+/-0.04 mg/dL and 3.38+/-0.51 mg/dL for the control and VCM-treated groups, respectively. Also, urinary excretion of NAG was increased after VCM injection. Besides, there was a significant dilatation of the renal tubules, eosinophilic casts within some tubules, desquamation and vacuolization of renal tubule epithelium, and interstitial tissue inflammation in VCM-treated rats. In VCM-treated rats, both PAR and PARP-1 expressions were increased in renal tubular cells. ISO treatment attenuated VCM-induced renal injury, as indicated by BUN and plasma creatinine levels, urinary NAG excretion, and renal histology. PARP inhibitor treatment also decreased PAR and PARP-1 protein expressions similar to that of controls. Herewith, the overactivation of the PARP pathway may have a role in VCM-induced renal impairment and pharmacological inhibition of this pathway might be an effective intervention to prevent VCM-induced acute renal injury.
Dalaklioglu
Selvinaz
S
Antalya Education and Research Hospital, Department of Pharmacology, 07070 Antalya, Turkey. selvidal77@hotmail.com.tr
Tekcan
Merih
M
Gungor
Nazli Ece
NE
Celik-Ozenci
Ciler
C
Aksoy
Nazif Hikmet
NH
Baykal
Asli
A
Tasatargil
Arda
A
D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003401:Creatine / Q000097:blood; D007546:Isoquinolines; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011804:Quinolines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014640:Vancomycin / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D015415:Biomarkers; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines; C095653:1,5-dihydroxyisoquinoline; D014640:Vancomycin; D011065:Poly(ADP-ribose) Polymerases; D000118:Acetylglucosaminidase; D003401:Creatine