The influence of the inducer of the transcription factor Nrf2 on metabolic parameters in rat tissues upon injection of hemin

Abstract

Heme is an essential cofactor involved in many biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, etc. However, excess free heme is highly toxic due to its ability to stimulate oxidative stress. One of the main responses of the body to oxidative stress is the formation of the transcription factor Nrf2, which enters the nucleus and stimulates the induction of genes encoding key proteins of the antioxidant defense system. Nrf2 is a redox-sensitive transcription factor that regulates the expression of genes containing the responsive element ARE in their promoters. Nrf2 is currently considered the main regulator of redox homeostasis, controlling the expression of over 100 genes involved in protection against reactive oxygen species and electrophiles. One of the inducers of the Nrf2 transcription factor is dimethyl fumarate (DMF), which induces endogenous antioxidant defense via the Nrf2 pathway. The effect of Nrf2 on nitrogen metabolism and the thiol system under oxidative stress remains insufficiently studied. In this regard, the aim of this study was to investigate nitrogen metabolism parameters and the content of non-protein thiols under conditions of hemin administration, the introduction of the Nrf2 transcription factor inducer dimethyl fumarate, as well as their combined administration. The study subjects were outbred white male rats weighing 180–260 g, which received intraperitoneal injections of hemin solution at a dose of 50 μg per kg of body weight and oral administration of dimethyl fumarate. After 24 hours, the animals were used in the experiment in accordance with the Convention on the Treatment of Animals. Blood plasma was obtained from collected blood samples. The liver was perfused with cooled physiological saline. Homogenates were prepared from the liver, kidneys, and heart, which were used to determine catalase, aminotransferase, and arginase activity, as well as the content of TBARS (thiobarbituric acid-reactive substances) and reduced SH-groups. Urea levels were determined in blood plasma. The study results indicate the following: hemin administration caused an increase in TBARS content in the heart, a decrease in reduced thiol levels in the rat organs, and catalase activation in the kidneys; dimethyl fumarate administration led to a decrease in TBARS levels in the heart, an increase in total thiol groups in the kidneys, and an increase in arginase activity in the liver; combined administration of hemin and DMF after 24 hours resulted in an increase in TBARS content in the kidneys and heart, non-protein SH-groups in the liver, plasma urea levels, as well as an increase in aminotransferase and arginase activity in the studied organs. These observed changes may reflect the activation of Nrf2 in the presence of a pro-oxidant factor and its effect on the expression of a number of genes whose products participate in adaptive processes under oxidative stress.