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Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.

ABSTRACT: To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury.Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury.Wild-type and Nrf2-deficient mice were treated with 15-deoxy-?(12,14)-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60-minute hepatic 70% ischemia, followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions.After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage; impaired GSTm1, NQO1, and GCLc inductions; disturbed redox state; and aggravated tumor necrosis factor ? mRNA expression in comparison with wild-type livers. 15d-PGJ2 treatment protected the livers of wild-type mice from I/R injury via increased expressions of GSTm1, NQO1, and GCLc; maintained redox status; and decreased tumor necrosis factor ? induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2(-/-) mice and were not annulled by peroxisome proliferator-activated receptor ? antagonist in Nrf2(+/+) mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response.Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.

SUBMITTER: Kudoh K

PROVIDER: S-EPMC4047210 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.

Kudoh Kazuhiro K Uchinami Hiroshi H Yoshioka Masato M Seki Ekihiro E Yamamoto Yuzo Y

Annals of surgery 20140701 1

<h4>Objective</h4>To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury.<h4>Background</h4>Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury.<h4>Methods</h4>Wild-type and Nrf2-deficient mice were treat ...[more]

PMID: 24368646

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Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

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Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.

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Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.

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