Renoprotective potency of amifostine in rat renal ischaemia-reperfusion.
OBJECTIVE
Kidneys from haemodynamically unstable donors may suffer from renal ischaemia-reperfusion (RIR) injury. RIR is associated with reactive oxygen species production that induces inflammation and activates the arachidonic acid (AA) pathway which converts AA into prostaglandin E(2). Amifostine was investigated for its renoprotective potential in RIR.


METHODS
The effect of amifostine (25 mg/kg  =  910 mg/m(2)) on the COX pathway, enzymatic antioxidant activity, the lipid peroxidation marker MDA, serum creatinine and apoptosis was determined in rats. Kidneys were subjected to 45 min of ischaemia and 1 or 24 h of reperfusion. Control groups (sham: coeliotomy, no ischaemia; r1: 45 min ischaemia/1 h reperfusion; r2: 45 min ischaemia/24 h reperfusion) were administered physiological saline intraperitoneally, and treated groups (E1: 45 min ischaemia/1 h reperfusion; E2: 45 min ischaemia/24 h reperfusion) received amifostine 30 min before reperfusion.


RESULTS
Serum creatinine increased in non-treated control rats: r1 vs sham (1.6-fold; P <0.007), r2 vs sham (2-fold; P <0.007). Amifostine decreased serum creatinine levels in treated rats: E1 vs r1 (8%; P <0.0025), E2 vs r2 (44%; P <0.0025). Amifostine reduced acute tubular necrosis (25%) 24 h after reperfusion: E1 vs r1 (P <0.004), E2 vs r2 (P <0.03) and reduced COX-2 and microsomal prostaglandin E synthase expression: E1 vs r1 (P <0.03), E2 vs r2 (P <0.02). Amifostine decreased MDA (P <0.04) and reduced caspase-3 expression but did not alter enzymatic antioxidant activity after RIR.


CONCLUSIONS
Amifostine decreased the degree and severity of tubular damage after reperfusion, probably by scavenging oxygen free radicals and attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.
Laboratoire de Chirurgie Expérimentale, UPRES EA 1602, Université Paris-Sud 11, APHP Hôpital Bicêtre, Faculté de Médecine, Le Kremlin-Bicêtre, France.
Mohammed Koussai
MK
Chok
Marc
M
Conti
Abdelhamid
A
Almolki
Sophie
S
Ferlicot
Sylvain
S
Loric
Antoine
A
Dürrbach
Gérard
G
Benoît
Stéphane
S
Droupy
Pascal
P
Eschwège
D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004999:Amifostine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003404:Creatinine / Q000097:blood; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D009336:Necrosis; D000071876:Prostaglandin-E Synthases; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome
D017382:Reactive Oxygen Species; D003404:Creatinine; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D004999:Amifostine