Overactivation of the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice.
Hepatic ischemia/reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element pathway in warm hepatic IRI. Nrf2 knockout (KO) and wild-type (WT) animals and novel transgenic mice expressing a constitutively active nuclear factor (erythroid-derived 2)-like 2 (caNrf2) mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were killed 6 hours after reperfusion, and their serum and tissue were collected for analysis. As compared to WT animals after ischemia/reperfusion (IR), Nrf2 KO mice had increased hepatocellular injury with increased serum alanine aminotransferase and aspartate aminotransferase, Suzuki score, apoptosis, an increased inflammatory infiltrate, and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte-specific Nrf2 overactivation providing protection against warm hepatic IRI.
Departments of Surgery, University of Wisconsin, Madison, WI.
Lung-Yi
LY
Lee
Departments of Surgery, University of Wisconsin, Madison, WI.
Calvin
C
Harberg
Departments of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI.|Pathology Services, William S. Middleton Memorial Hospital, U.S. Department of Veterans Affairs, Madison, WI.
Kristina A
KA
Matkowskyj
Departments of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI.
Shelly
S
Cook
Departments of Surgery, University of Wisconsin, Madison, WI.
Drew
D
Roenneburg
Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland.
Sabine
S
Werner
Divisions of Pharmaceutical Sciences, University of Wisconsin, Madison, WI.|Divisions of Molecular and Environmental Toxicological Center, University of Wisconsin, Madison, WI.|Center for Neuroscience, University of Wisconsin, Madison, WI.|Waisman Center, University of Wisconsin, Madison, WI.
Jeffrey
J
Johnson
Departments of Surgery, University of Wisconsin, Madison, WI.|Surgical Services, William S. Middleton Memorial Hospital, U.S. Department of Veterans Affairs, Madison, WI.
David P
DP
Foley
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000098:blood supply*; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse