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

• Published in: PeerJ (San Francisco, CA) CA), 2021-11, Vol.9, p.e12426-e12426, Article e12426
• Main Authors: Cienfuegos-Pecina, Eduardo, Moreno-Peña, Diana P, Torres-González, Liliana, Rodríguez-Rodríguez, Diana Raquel, Garza-Villarreal, Diana, Mendoza-Hernández, Oscar H, Flores-Cantú, Raul Alejandro, Samaniego Sáenz, Brenda Alejandra, Alarcon-Galvan, Gabriela, Muñoz-Espinosa, Linda E, Ibarra-Rivera, Tannya R, Saucedo, Alma L, Cordero-Pérez, Paula
• Format: Article
• Language: English
• Subjects: 2-hydroxyglutarate; Acids; Animal models; Animals; Bilirubin; Biochemical markers; Biochemistry; Biomarkers; Dehydrogenases; Enzymes; Gastroenterology and Hepatology; Glutathione peroxidase; Hmox1; Hydroxylases; Hypoxia; Hypoxia-inducible factors; IL-1β; Interleukin 6; Ischemia; Ischemia-reperfusion injury; Kidney transplants; Laparotomy; Liver; Liver diseases; Liver transplantation; Malondialdehyde; Molecular Biology; NMR; Nuclear magnetic resonance; Oxidative stress; Pharmacology; Prevention; Proinflammatory cytokines; Reperfusion; Sample size; Spectrum analysis; Standard deviation; Superoxide dismutase; Toxicity; Transplantation; Tumor necrosis factor; Vegfa
• ISSN: 2167-8359; 2167-8359
• DOI: 10.7717/peerj.12426

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. 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. 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.