Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
Eduardo Cienfuegos-Pecina,
Diana P. Moreno-Peña,
Liliana Torres-González,
Diana Raquel Rodríguez-Rodríguez,
Diana Garza-Villarreal,
Oscar H. Mendoza-Hernández,
Raul Alejandro Flores-Cantú,
Brenda Alejandra Samaniego Sáenz,
Gabriela Alarcon-Galvan,
Linda E. Muñoz-Espinosa,
Tannya R. Ibarra-Rivera,
Alma L. Saucedo,
Paula Cordero-Pérez
Affiliations
Eduardo Cienfuegos-Pecina
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Diana P. Moreno-Peña
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Liliana Torres-González
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Diana Raquel Rodríguez-Rodríguez
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Diana Garza-Villarreal
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Oscar H. Mendoza-Hernández
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Raul Alejandro Flores-Cantú
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Brenda Alejandra Samaniego Sáenz
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Gabriela Alarcon-Galvan
Universidad de Monterrey, Basic Science Department, School of Medicine, Monterrey, Nuevo León, Mexico
Linda E. Muñoz-Espinosa
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
Tannya R. Ibarra-Rivera
Universidad Autónoma de Nuevo León. Department of Analytical Chemistry, School of Medicine, Monterrey, Nuevo León, Mexico
Alma L. Saucedo
Universidad Autónoma de Nuevo León. Department of Analytical Chemistry, School of Medicine, Monterrey, Nuevo León, Mexico
Paula Cordero-Pérez
Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital “Dr. José E. González”, Monterrey, Nuevo León, Mexico
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 (S)-2-hydroxyglutarate [(S)-2HG] on liver IR injury in Wistar rats. Methods Twenty-eight female Wistar rats were divided into the following groups: sham (SH, n = 7), non-toxicity (HGTox, n = 7, 25 mg/kg of (S)-2HG, twice per day for two days), IR (n = 7, total liver ischemia: 20 minutes, reperfusion: 60 minutes), and (S)-2HG+IR (HGIR, n = 7, 25 mg/kg of (S)-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 Hmox1, Vegfa, and Pdk1, 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 (S)-2HG did not cause any alteration in the assessed biochemical markers compared to SH. Preconditioning with (S)-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 (S)-2HG tended to decrease the severity of hepatocyte necrosis and sinusoidal congestion compared to the IR group. The administration of (S)-2HG did not affect the expression of Hmox1 but decreased the expression of both Vegfa and Pdk1 compared to the SH group, suggesting that the HIF-1 pathway is not involved in its mechanism of hepatoprotection. In conclusion, (S)-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.