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Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury.

ABSTRACT: Hepatic ischemia-reperfusion injury is seen in a variety of clinical conditions, including hepatic thrombosis, systemic hypotension, and liver transplantation. Calcium (Ca²⁺) signaling mediates several pathophysiological processes in the liver, but it is not known whether and how intracellular Ca²⁺ channels are involved in the hepatocellular events secondary to ischemia-reperfusion. Using an animal model of hepatic ischemia-reperfusion injury, we observed a progressive increase in expression of the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular Ca²⁺ channel that is not normally expressed in healthy hepatocytes. ITPR3 expression was upregulated, at least in part, by a combination of demethylation of the ITPR3 promoter region and the increased transcriptional activity of the nuclear factor of activated T-cells (NFAT). Additionally, expression of pro-inflammatory interleukins and necrotic surface area were less pronounced in livers of control animals compared to liver-specific ITPR3 KO mice subjected to hepatic damage. Corroborating these findings, ITPR3 expression and activation of NFAT were observed in hepatocytes of liver biopsies from patients who underwent liver ischemia caused by thrombosis after organ transplant. Together, these results are consistent with the idea that ITPR3 expression in hepatocytes plays a protective role during hepatic injury induced by ischemia-reperfusion.

SUBMITTER: Lima Filho ACM

PROVIDER: S-EPMC7530136 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury.

Lima Filho Antônio Carlos Melo ACM França Andressa A Florentino Rodrigo M RM Dos Santos Marcone Loiola ML de Oliveira Lemos Fernanda F Missiaggia Dabny Goulart DG Fonseca Roberta Cristelli RC Fonseca Roberta Cristelli RC Gustavo Oliveira André A Ananthanarayanan Meenakshisundaram M Guerra Mateus T MT de Castro Fonseca Matheus M Vidigal Paula Vieira Teixeira PVT Lima Cristiano Xavier CX Nathanson Michael H MH Fatima Leite M M

Cell calcium 20200811

Hepatic ischemia-reperfusion injury is seen in a variety of clinical conditions, including hepatic thrombosis, systemic hypotension, and liver transplantation. Calcium (Ca<sup>2+</sup>) signaling mediates several pathophysiological processes in the liver, but it is not known whether and how intracellular Ca<sup>2+</sup> channels are involved in the hepatocellular events secondary to ischemia-reperfusion. Using an animal model of hepatic ischemia-reperfusion injury, we observed a progressive incr ...[more]

PMID: 32957029

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Project description:BackgroundHepatic ischemia and reperfusion (I/R) injury is of common occurrence during liver surgery and transplantation, isosteviol (ISV) is an acid hydrolysate of stevioside, the major component of Stevia rebaudiana. Stevioside and its metabolites have been shown to have varieties of pharmacological activities, However, the effect of ISV on hepatic I/R injury has not determined. The purpose of this paper is to study the effect of ISV on mice with hepatic I/R injury and further investigate its underlying mechanism.MethodsThe blood vessels supplying the left/middle lobe of the liver in mice were clamped to cause liver ischemia for 1h, and then removed the clamp to conduct reperfusion for 6 h. ISV or saline was injected intraperitoneally after reperfusion. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10 in serum and tissues were evaluated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The infiltration of neutrophils and macrophages into the liver tissue was determined by flow cytometry and myeloperoxidase. Liver hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) and Annexin V probe were used to determine liver injury and hepatocyte apoptosis. western blots (WB) was used to investigate the activation of nuclear factor kappa-B (NF-κB) and c-JunNH2 terminal kinase (JNK), p38 and extracellular regulated protein kinase (ERK), while the expression of apoptosis-related proteins B-cell lymphoma-2 (BCL-2), BCL2-associated X protein (BAX), caspase-3 was detected.ResultsISV reduced aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to alleviate liver injury. ISV significantly reduced the release of inflammatory cytokines and the accumulation of liver neutrophils and macrophages. Meanwhile, ISV can promote the expression of anti-apoptosis-related protein BCL-2 and inhibit the expression of pro-apoptotic protein BAX and the activation of the protease caspase-3, and reduce the occurrence of hepatocyte apoptosis. Finally, ISV can reduce the phosphorylation level and activation of NF-κB, JNK, p38 and ERK.ConclusionsISV inhibits the occurrence of inflammation and hepatocyte apoptosis through mitogen-activated protein kinase (MAPK)/NF-κB signaling pathway to relieve liver injury.

Dataset Information

Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury.

Publications

Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury.

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