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Selective nuclear factor κ‐B inhibitors, pyrolidium dithiocarbamate and sulfasalazine, prevent the nephrotoxicity induced by gentamicin
Author(s) -
TUGCU VOLKAN,
OZBEK EMIN,
TASCI ALI I.,
KEMAHLI ERAY,
SOMAY ADNAN,
BAS MUZAFFER,
KARACA CETIN,
ALTUG TUNCAY,
ÇEKMEN MUSTAFA B.,
ÖZDOGAN HACI K.
Publication year - 2006
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2006.06321.x
Subject(s) - nephrotoxicity , gentamicin , nitric oxide synthase , chemistry , malondialdehyde , renal cortex , creatinine , endocrinology , intraperitoneal injection , medicine , pharmacology , nitric oxide , kidney , oxidative stress , biochemistry , antibiotics
OBJECTIVE To investigate the effect of selective nuclear factor κ‐B (NFκ‐B) inhibitors, pyrolidium dithiocarbamate (PD) and sulfasalazine (SZ) on renal tubular necrosis and inducible nitric oxide synthase (iNOS) and NFκ‐B expression induced by gentamicin in rats. MATERIALS AND METHODS In all, 48 adult male Sprague‐Dawley rats were divided into six equal groups; group 1, control; group 2, injected with gentamicin for 10 days (100 mg/kg/day, intraperitoneal, i.p.); group 3, injected with gentamicin plus PD (100 mg/kg/day, i.p.); group 4, injected with gentamicin plus SZ (75 mg/kg/day, i.p.); group 5, injected with gentamicin plus distilled water (vehicle for PD); and group 6, injected with gentamicin plus ammonium hydroxide (75 mg/day, 1 m , vehicle for SZ) for 10 days. At 24 h after the last injection, rats were killed and the renal cortex separated from the medulla. A small sample was fixed in formaldehyde solution for histological and immunohistochemical examination. Blood samples were also taken to assess the serum levels of urea, creatinine, Na + , K + and γ‐glutamyl transpeptidase (GT). Crude extracts of the cortex were used to determine reduced glutathione (GSH‐Px), NO and malondialdehyde (MDA). Immunohistochemically, iNOS and the active subunit of NFκB, P65, were evaluated using mouse monoclonal antibodies. RESULTS On haematoxylin and eosin staining, compared with the controls rats, gentamicin caused widespread tubular necrosis (grade 3 and 4) but in group 3 and 4 there was a marked reduction in the extent of tubular damage. Immunohistochemically there was more marked staining for iNOS and P65 expression in rats given gentamicin than in the control and group 3 and 4 ( P < 0.001). In groups 3 and 4 iNOS and P65 expression were significantly less than in rats given only gentamicin. There was no significant difference in serum levels of Na + , K + , blood urea nitrogen and creatinine. Compared with control rats, gentamicin caused hyperproteinuria, a marked increase in levels of serum γ‐GT, MDA and NO, and a decrease in GSH‐Px ( P < 0.001). CONCLUSION These results indicate that gentamicin induces iNOS expression through activation of NFκ‐B (P65). It is possible to prevent gentamicin‐induced nephrotoxicity using selective NFκ‐B inhibitors.