In:
PeerJ, PeerJ, Vol. 9 ( 2021-11-12), p. e12426-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2167-8359
DOI:
10.7717/peerj.12426/fig-1
DOI:
10.7717/peerj.12426/fig-2
DOI:
10.7717/peerj.12426/fig-3
DOI:
10.7717/peerj.12426/fig-4
DOI:
10.7717/peerj.12426/table-1
DOI:
10.7717/peerj.12426/table-2
DOI:
10.7717/peerj.12426/supp-1
DOI:
10.7717/peerj.12426/supp-2
DOI:
10.7717/peerj.12426/supp-3
DOI:
10.7717/peerj.12426/supp-4
DOI:
10.7717/peerj.12426/supp-5
DOI:
10.7717/peerj.12426/supp-6
DOI:
10.7717/peerj.12426/supp-7
DOI:
10.7717/peerj.12426/supp-8
DOI:
10.7717/peerj.12426/supp-9
Language:
English
Publisher:
PeerJ
Publication Date:
2021
detail.hit.zdb_id:
2703241-3
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