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Hepatic Ischemia-Reperfusion Induces Renal Heme Oxygenase-1 via NF-E2-Related Factor 2 in Rats and Mice

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas

Hepatic ischemia-reperfusion (IR) results in Kupffer cell activation and subsequent tumor necrosis factor (TNF) release, leading to localized hepatic injury and remote organ dysfunction. Heme oxygenase (HO)-1 is an enzyme that is induced by various stimuli, including proinflammatory cytokines, and exerts antioxidative and anti-inflammatory functions. Up-regulation of HO-1 is known to protect against hepatic IR injury, but the effects of hepatic IR on the kidney are poorly understood. Thus, the purpose of this study was to determine whether hepatic IR and resultant Kupffer cell activation alters renal HO-1 expression. Male Sprague-Dawley rats and wild-type and NF-E2-related factor 2 (Nrf2)-null mice were subjected to 60 min of partial hepatic ischemia, and at various times thereafter, blood, liver, and kidneys were collected. After reperfusion, 1) creatinine clearance decreased; 2) HO-1 mRNA and protein expression in liver and kidney markedly increased; 3) renal NAD(P)H: quinone oxidoreductase 1 mRNA expression was induced; 4) serum TNF levels increased; 5) Nrf2 translocation into the nucleus of renal tissue increased; and 6) renal and urinary 15-deoxy-^12,14-prostaglandin J₂ (15-d-PGJ₂) levels increased. Kupffer cell depletion by pretreating with gadolinium chloride 1) attenuated increased mRNA expression of HO-1 in kidney; 2) attenuated the increase in TNF; 3) inhibited the increase in Nrf2 nuclear translocation; and 4) tended to attenuate renal 15-d-PGJ₂ levels. Whereas renal HO-1 mRNA expression increased in wild-type mice, it was attenuated in Nrf2-null mice. These results suggest that renal HO-1 is induced via Nrf2 to protect the kidney from remote organ injury after hepatic IR.

Address correspondence to: Dr. Curtis D. Klaassen, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7417. E-mail: cklaasse{at}kumc.edu

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