Rac2 deficiency attenuates CCl-induced liver injury through suppressing inflammation and oxidative stress.

Oxidative stress is a leading cause to liver injury. Rac2 is a Ras-associated guanosine triphosphatase, an important molecule modulating a large number of cells and involved in the regulation of reactive oxygen species (ROS). For the study described here, we supposed that Rac2 knockout protects mice against CCl-induced acute liver injury. We found that Rac2 expressed highly in CCl-induced liver tissues. CCl-treated Rac2 knockout (Rac2-/-) mice had reduced CD24 levels and steatosis. In addition, CCl-induced high expression of pro-inflammatory cytokines and chemokine were reversed by Rac2 deficiency compared to CCl-treated wild type (WT) mice. We also found that fibrosis-related signals of MMP-9, MMP-2 and TGF-β1 were also down-regulated in Rac2 knockout mice induced by CCl. Significantly, oxidative stress induced by CCl was also suppressed owing to the lack of Rac2, evidenced by enhanced superoxide dismutase (SOD) activity, and reduced malondialdehyde (MDA) levels, superoxide radical, HO, xanthine oxidase (XO), xanthine dehydrogenase (XDH) and XO/XDH ratio. Moreover, c-Jun N-terminal protein kinase mitogen-activated protein kinases (JNK MAPK) was activated by CCl, which was reversed in the liver of Rac2-/- mice through western blot and immunohistochemical analysis. In vitro, endotoxin (LPS) was treated to hepatocytes isolated from WT mice and Rac2-/- mice. The data further confirmed the role of Rac2 deficiency suppressed pro-inflammatory cytokines and chemokine, as well as fibrosis-related signals. Of note, production of ROS induced by LPS was reduced in Rac2-/- cells, accompanied with enhanced SOD1, SOD2 and reduced XO and phosphorylated-JNK expressions. Our results indicated that Rac2 played an essential role in acute liver injury induced by CCl, providing the compelling information of the effects of Rac2 on liver injury, and revealing a novel regulatory mechanism for acute liver injury.