Treatment with sodium ()-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats.

BACKGROUND

Ischemia-reperfusion (IR) injury is one of the leading causes of early graft dysfunction in liver transplantation. Techniques such as ischemic preconditioning protect the graft through the activation of the hypoxia-inducible factors (HIF), which are downregulated by the EGLN family of prolyl-4-hydroxylases, a potential biological target for the development of strategies based on pharmacological preconditioning. For that reason, this study aims to evaluate the effect of the EGLN inhibitor sodium ()-2-hydroxyglutarate [()-2HG] on liver IR injury in Wistar rats.

METHODS

Twenty-eight female Wistar rats were divided into the following groups: sham (SH,  = 7), non-toxicity (HGTox,  = 7, 25 mg/kg of ()-2HG, twice per day for two days), IR ( = 7, total liver ischemia: 20 minutes, reperfusion: 60 minutes), and ()-2HG+IR (HGIR,  = 7, 25 mg/kg of ()-2HG, twice per day for two days, total liver ischemia as the IR group). Serum ALT, AST, LDH, ALP, glucose, and total bilirubin were assessed. The concentrations of IL-1β, IL-6, TNF, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured in liver tissue, as well as the expression of , , and , determined by RT-qPCR. Sections of liver tissue were evaluated histologically, assessing the severity of necrosis, sinusoidal congestion, and cytoplasmatic vacuolization.

RESULTS

The administration of ()-2HG did not cause any alteration in the assessed biochemical markers compared to SH. Preconditioning with ()-2HG significantly ameliorated IR injury in the HGIR group, decreasing the serum activities of ALT, AST, and LDH, and the tissue concentrations of IL-1β and IL-6 compared to the IR group. IR injury decreased serum glucose compared to SH. There were no differences in the other biomarkers assessed. The treatment with ()-2HG tended to decrease the severity of hepatocyte necrosis and sinusoidal congestion compared to the IR group. The administration of ()-2HG did not affect the expression of but decreased the expression of both and compared to the SH group, suggesting that the HIF-1 pathway is not involved in its mechanism of hepatoprotection. In conclusion, ()-2HG showed a hepatoprotective effect, decreasing the levels of liver injury and inflammation biomarkers, without evidence of the involvement of the HIF-1 pathway. No hepatotoxic effect was observed at the tested dose.