Heme oxygenase-1 ameliorates kidney ischemia-reperfusion injury in mice through extracellular signal-regulated kinase 1/2-enhanced tubular epithelium proliferation

• Induction of HO-1 in renal tubules activates the MEK-ERK pathway.
• ZnPP inhibition of HO-1 activity leads to a reduction of phosphorylated ERK1/2.
• HO-1 preconditioning rescues kidney function after renal IRI by activating ERK1/2.
• HO-1 preconditioning enhances tubular recovery and protects further kidney injury.

Heme oxygenase (HO)-1 confers transient resistance against oxidative damage, including renal ischemia-reperfusion injury (IRI). We investigated the potential protective effect of HO-1 induction in a mouse model of renal IRI induced by bilateral clamping of the kidney arteries. The mice were randomly assigned to five groups to receive an intraperitoneal injection of PBS, hemin (an HO-1 inducer, 100 μmol/kg), hemin + ZnPP (an HO-1 inhibitor, 5 mg/kg), hemin + PD98059 (a MEK-ERK inhibitor, 10 mg/kg) or a sham operation. All of the groups except for the sham-operated group underwent 25 min of ischemia and 24 to 72 h of reperfusion. Renal function and tubular damage were assessed in the mice that received hemin or the vehicle treatment prior to IRI. The renal injury score and HO-1 protein levels were evaluated via H&E and immunohistochemistry staining. Hemin-preconditioned mice exhibited preserved renal cell function (BUN: 40 ± 2 mg/dl, creatinine: 0.53 ± 0.06 mg/dl), and the tubular injury score at 72 h (1.65 ± 0.12) indicated that tubular damage was prevented. Induction of HO-1 induced the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. However, these effects were abolished with ZnPP treatment. Kidney function (BUN: 176 ± 49 mg/dl, creatinine: 1.54 ± 0.39 mg/dl) increased, and the tubular injury score (3.73 ± 0.09) indicated that tubular damage also increased with ZnPP treatment. HO-1-induced tubular epithelial proliferation was attenuated by PD98059. Our findings suggest that HO-1 preconditioning promotes ERK1/2 phosphorylation and enhances tubular recovery, which subsequently prevents further renal injury.

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