Renoprotective potency of heme oxygenase-1 induction in rat renal ischemia-reperfusion.
OBJECTIVE
Renal injury caused by ischemia-reperfusion (IR) can lead to acute renal failure or delayed graft function. Renal ischemia-reperfusion (RIR) induces inflammatory disorders via activation of arachidonic acid metabolism into prostaglandin E(2) (PGE(2)). Two inducible enzymes, COX-2 and microsomal prostaglandin E synthase (mPGES), regulate PGE(2) production. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated during cellular stress. Overexpression of HO-1 is beneficial in transplantation models including antigen-independent IR injury, acute and chronic allograft rejection.


METHODS
We investigated the effect of HO-1 induction on the COX pathway, antioxidant enzyme activities, malondialdehyde (MDA) levels, and apoptosis in rat kidneys subjected to 45 min ischemia and 1 h or 24 h reperfusion. Rats were injected intraperitoneally with either: 50 mg/kg hemin (HO-1 inducer groups: H1, H2); 50 micromol/kg ZnPP (HO-1 inhibitor groups: Hz1, Hz2); or 0.9% saline (control groups: r1, r2). Sham animals (Sh) did not undergo RIR.


RESULTS
Serum creatinine increased significantly after RIR (r vs Sh; p <0.05). Hemin treatment induced a significant decrease in serum creatinine after RIR (H vs r; p <0.05) whereas ZnPP treatment significantly increased serum creatinine levels (Sh vs Hz; p <0.05). Hemin reduced the severity of acute tubular necrosis and significantly reduced COX-2 and mPGES expression (p <0.05). Hemin did not alter depleted antioxidant enzyme activity but did decrease levels of MDA (p <0.05). Hemin also reduced caspase-3 expression.


CONCLUSIONS
HO-1 decreased the degree and severity of tubular damage after IR, probably by attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.
Chok
Mohammed Koussai
MK
Laboratoire de Chirurgie Expérimentale, UPRES EA 1602, Université Paris-Sud 11, Faculté de Médecine, Le Kremlin Bicêtre, France. peschwege@yahoo.com
Ferlicot
Sophie
S
Conti
Marc
M
Almolki
Abdelhamid
A
Dürrbach
Antoine
A
Loric
Sylvain
S
Benoît
Gérard
G
Droupy
Stéphane
S
Eschwège
Pascal
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000276:immunology / Q000378:metabolism*; D011524:Protoporphyrins / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
D011524:Protoporphyrins; C017803:zinc protoporphyrin; D008315:Malondialdehyde; D006427:Hemin; D003404:Creatinine; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D053148:Caspase 3