N-acetylcysteine attenuates NSAID-induced rat renal failure by restoring intrarenal prostaglandin synthesis.
BACKGROUND
Renal failure is a threatening side-effect of NSAID administration, consequent to NSAID-mediated abrogation of prostaglandin synthesis and resultant renal ischaemia. N-acetylcysteine (NAC) has renoprotective properties. We examined effects of NAC in a rat model of NSAID-induced renal failure.


METHODS
Renal failure was generated in 80 rats by 6-day water deprivation and 3-day 15 mg/kg/day diclofenac injection. The rats were concomitantly treated, or not, by NAC, 40 mg/kg/day. Renal function was evaluated by cystatin C, creatinine and urea. Intrarenal blood flow was measured by laser Doppler. The kidneys were subjected to pathological examination or evaluation of intrarenal NO, H2O2 and PGE2.


RESULTS
NAC significantly attenuated deterioration of renal function in diclofenac-treated rats: cystatin C dropped from 2.8+/-0.35 to 2.2+/-0.67 mg/l, P=0.016; creatinine from 1.2+/-0.97 to 0.96+/-0.19 mg/dl, P=0.02; urea from 208.4+/-57.9 to 157.6+/-33.7 mg/dl, P=0.028. Diclofenac-inflicted hystopathological damage was significantly reduced following NAC treatment. Intrarenal medullar blood flow dropped by 51+/-12.4% in diclofenac-treated rats, but only by 14+/-3.39% in those receiving NAC after diclofenac injection (P<0.001). H2O2 was elevated in renal tissues of diclofenac-receiving rats, while decreased in NAC-treated animals. PGE2 release by diclofenac-treated rats dropped significantly, but was restored after NAC administration both in renal cortices (144.7+/-10.4 vs 19.7+/-1.5 pmol/ml, P<0.001) and medullae (148.5+/-7.3 vs 66.6+/-7.3 pmol/ml, P<0.001).


CONCLUSIONS
In this model of renal failure induced by NSAID administration combined with water deprivation, NAC treatment successfully attenuated the deterioration of renal function by inducing renal vasodilatation, decreasing oxidative stress via inhibition of intrarenal ROS content and restoration of intrarenal PGE2 release back to the basal levels.
Efrati
Shai
S
Nephrology Division, Research & Development Unit, Department of Internal Medicine A, Assaf Harofeh Medical Center, Zerifin 70300, and Sackler Faculty of Medicine, Tel Aviv University, Israel. efratishai@013.net
Berman
Sylvia
S
Siman-Tov
Yariv
Y
Lotan
Raffie
R
Averbukh
Zhan
Z
Weissgarten
Joshua
J
Golik
Ahuva
A
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019610:Cytoprotection; D004008:Diclofenac; D015232:Dinoprostone / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000098:blood supply / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D014018:Tissue Distribution
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D006861:Hydrogen Peroxide; D015232:Dinoprostone; D000111:Acetylcysteine