Dietary Inorganic Nitrate Protects Hepatic Ischemia-Reperfusion Injury Through NRF2-Mediated Antioxidative Stress.

Shaorong Li,Chunmei Zhang,Guangyong Sun,Hua Jin,Hufeng Xu,Dong Zhang,Songlin Wang,Jinsong Wang

doi:10.3389/fphar.2021.634115

Shaorong Li, Chunmei Zhang + Show 6 more

Open Access

https://doi.org/10.3389/fphar.2021.634115

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Abstract

Objectives: Hepatic ischemia-reperfusion injury (HIRI) is of common occurrence during liver surgery and liver transplantation and may cause hepatic impairment, resulting in acute liver dysfunction. Nitrate plays an important physiological regulatory role in the human body. Whether dietary nitrate could prevent HIRI is, however, unknown. Methods: A HIRI mouse model was established in that the blood supply to the median lobe and left lateral lobe was blocked for 60 min through the portal vein and related structures using an atraumatic clip. Sodium nitrate (4 mM) was administrated in advance through drinking water to compare the influence of sodium nitrate and normal water on HIRI. Results: Liver necrosis and injury aggravated after HIRI. The group treated with sodium nitrate showed the lowest activities of plasma aminotransferase and lactate dehydrogenase and improved outcomes in histological investigation and TUNEL assay. Mechanistically, sodium nitrate intake increased plasma and liver nitric oxide levels, upregulated nuclear factor erythroid 2-related factor 2 (NRF2)–related molecules to reduce malondialdehyde level, and increased the activities of antioxidant enzymes to modulate hepatic oxidative stress. Conclusions: Dietary inorganic nitrate could prevent HIRI, possibly by activating the NRF2 pathway and modulating oxidative stress. Our study provides a novel therapeutic compound that could potentially prevent HIRI during liver transplantation or hepatic surgery.

Highlights

Hepatic ischemia-reperfusion injury (HIRI) is common during liver resection or transplantation, which remains a major cause of hepatic failure following hepatic surgery (Mendes-Braz et al, 2012)
The water intake, food intake, and body weight of each mouse were detected (Supplementary Figure S1), while no difference was found among the groups
Mice exposed to 4 mM nitrate for 5 days prior to HIRI showed a significant decrease in the activities of ALT, AST, and Lactate Dehydrogenase (LDH) as compared with unpretreated mice

Summary

Introduction

Hepatic ischemia-reperfusion injury (HIRI) is common during liver resection or transplantation, which remains a major cause of hepatic failure following hepatic surgery (Mendes-Braz et al, 2012). A series of pathological alterations are referred to liver ischemia-reperfusion (IR) injury, including initial sterile hypoxic or ischemic tissue injury, reperfusion-induced oxidative stress, inflammatory response, and microvascular dysfunction (MassipSalcedo et al, 2007), and effective prevention or treatment methods are still lacking in clinics. Reduced bioavailability of NO can lead to endothelial and microvascular functional imbalance, bringing about the “noreflow phenomenon” after ischemic tissue reperfusion is initiated (Eltzschig and Eckle, 2011). Safe and effective methods to reduce oxidative stress, alleviate inflammation, and maintain NO bioavailability may become a new strategy for the prevention and treatment of hepatic IR injury

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