Received for publication July 20, 2006.
Revised December 5, 2006.
Accepted for publication December 5, 2006.

HEPATIC ISCHEMIA-REPERFUSION INDUCES RENAL HEME OXYGENASE-1 (HO-1) VIA NF-E2-RELATED FACTOR 2 (Nrf2) IN RATS AND MICE

Abstract

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 anti-oxidative 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 (NQO1) 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.

Key words: Tumor necrosis factor, DNA binding sites, Kupffer cells, Cyclooxygenases, Oxidative stress, Knockout, Ischemia/Reperfusion

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