Treatment with sodium (S)-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 pro...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	PeerJ Inc. 2021
Materias:	Ischemia-reperfusion injury 2-hydroxyglutarate Oxidative stress Proinflammatory cytokines Hmox1 Vegfa Medicine R
Acceso en línea:	https://doaj.org/article/0f9580f0de1b472dae1180650ebbcd4e
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spelling	oai:doaj.org-article:0f9580f0de1b472dae1180650ebbcd4e2021-11-14T15:05:11ZTreatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats10.7717/peerj.124262167-8359https://doaj.org/article/0f9580f0de1b472dae1180650ebbcd4e2021-11-01T00:00:00Zhttps://peerj.com/articles/12426.pdfhttps://peerj.com/articles/12426/https://doaj.org/toc/2167-8359Background 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.Eduardo Cienfuegos-PecinaDiana P. Moreno-PeñaLiliana Torres-GonzálezDiana Raquel Rodríguez-RodríguezDiana Garza-VillarrealOscar H. Mendoza-HernándezRaul Alejandro Flores-CantúBrenda Alejandra Samaniego SáenzGabriela Alarcon-GalvanLinda E. Muñoz-EspinosaTannya R. Ibarra-RiveraAlma L. SaucedoPaula Cordero-PérezPeerJ Inc.articleIschemia-reperfusion injury2-hydroxyglutarateOxidative stressProinflammatory cytokinesHmox1VegfaMedicineRENPeerJ, Vol 9, p e12426 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Ischemia-reperfusion injury 2-hydroxyglutarate Oxidative stress Proinflammatory cytokines Hmox1 Vegfa Medicine R
spellingShingle	Ischemia-reperfusion injury 2-hydroxyglutarate Oxidative stress Proinflammatory cytokines Hmox1 Vegfa Medicine R 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 Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
description	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.
format	article
author	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
author_facet	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
author_sort	Eduardo Cienfuegos-Pecina
title	Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
title_short	Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
title_full	Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
title_fullStr	Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
title_full_unstemmed	Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats
title_sort	treatment with sodium (s)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female wistar rats
publisher	PeerJ Inc.
publishDate	2021
url	https://doaj.org/article/0f9580f0de1b472dae1180650ebbcd4e
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Treatment with sodium (S)-2-hydroxyglutarate prevents liver injury in an ischemia-reperfusion model in female Wistar rats

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