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

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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.

Original languageEnglish
Article numbere12426
Pages (from-to)e12426
Publication statusPublished - 12 Nov 2021

Bibliographical note

Publisher Copyright:
Copyright 2021 Cienfuegos-Pecina et al.

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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