Abstract
Purpose: 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 E2 (PGE2). Two inducible enzymes, COX-2 and microsomal prostaglandin E synthase (mPGES), regulate PGE2 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. Materials and 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 μmol/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.
Keywords: Kidney, ischemia-reperfusion, reactive oxygen species, cyclooxygenase, amifostine
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