Overactivation of the nuclear factor (erythroid‐derived 2)–like 2–antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice

Abstract

Background and Aims 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 Nrf2-antioxidant response element pathway in warm hepatic IRI. Methods Nrf2 KO and WT animals, and novel transgenic mice expressing a constitutively active Nrf2 mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were sacrificed 6 hours after reperfusion and their serum and tissue collected for analysis. Results As compared to wild type animals after IR, Nrf2 KO mice had increased hepatocellular injury with increased serum ALT and AST, 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. Conclusion 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 over-activation providing protection against warm hepatic IRI.

Cell‐specific overactivation of nuclear erythroid 2 p45‐related factor 2–mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury

“…A recent study demonstrated that transgenic overexpression of Nrf2 in hepatocytes of lean donor livers can protect those livers from hepatocellular damage sustained after liver transplantation . We have recently shown that overactivation of Nrf2 in hepatocytes leads to reduced cellular damage after IRI . However, the study described here is the first to look at the role of direct, cell‐specific overactivation of Nrf2 in nonparenchymal cells in a model of warm hepatic IRI.…”

“…(11) We have recently shown that overactivation of Nrf2 in hepatocytes leads to reduced cellular damage after IRI. (10) However, the study described here is the first to look at the role of direct, cell-specific overactivation of Nrf2 in nonparenchymal cells in a model of warm hepatic IRI. By using novel transgenic mice, we intended to more precisely decipher the cell-specific role of Nrf2 in hepatic IRI.…”

“…Previous studies have demonstrated a protective role of Nrf2 in the setting of hepatic IRI. The global absence of Nrf2 results in increased cellular damage seen during warm hepatic IRI . Overactivation of Nrf2 in hepatocytes through expression of a constitutively active mutant in these cells leads to a reduction of hepatocellular damage after warm hepatic IRI .…”

“…The global absence of Nrf2 results in increased cellular damage seen during warm hepatic IRI . Overactivation of Nrf2 in hepatocytes through expression of a constitutively active mutant in these cells leads to a reduction of hepatocellular damage after warm hepatic IRI . In addition, overactivation of Nrf2 in hepatocytes of donor livers using hepatocyte‐specific KEAP1‐knockdown mice leads to a reduction in cold preservation‐IRI in a murine liver transplant model .…”

“…(9,10) Overactivation of Nrf2 in hepatocytes through expression of a constitutively active mutant in these cells leads to a reduction of hepatocellular damage after warm hepatic IRI. (10) In addition, overactivation of Nrf2 in hepatocytes of donor livers using hepatocytespecific KEAP1-knockdown mice leads to a reduction in cold preservation-IRI in a murine liver transplant model. (11) Despite these Nrf2-dependent protective effects, the selective impact of Nrf2 activation in nonparenchymal cells of the liver during IRI remains unclear.…”