The relationship between Nrf2/Keap1 system and endoplasmic reticulum stress and inflammatory markers in peripheral blood mononuclear cells of type 2 diabetic subjects

Abstract

Background: Oxidative stress, endoplasmic reticulum stress (ER stress), and inflammation are the main leading factors in the pathogenesis of type 2 diabetes. Nuclear factor erythroid 2-related factor 2/ Kelch-like ECH-associated protein 1 (Nrf2/Keap1) is the chief regulator of the antioxidant defense system that protects the cells against reactive oxygen species (ROS). ER stress and inflammatory pathways are involved in the suppression or the activation of the Nrf2/Keap1 system. In this study, we aimed to explore the possible relationships of the main factors contributing to oxidative stress, endoplasmic reticulum stress, and inflammation in peripheral blood mononuclear cells (PBMCs) of diabetic patients. Methods: Levels of biological parameters, oxidative stress markers as well as the gene transcription of Nrf2, Keap1, p22phox, Chop1, Grp78, IL-6, and TNF- were analyzed in the PBMCs of 32 type 2 diabetic and 31 non-diabetic subjects. The correlation analysis was performed for the markers of oxidative stress with selected ER stress-related genes and pro-inflammatory cytokines. Results: Fasting blood sugar (P<0.0001), HbA1c (P<0.0001), serum triglycerides (P = 0.024), insulin (P = 0.003), and HOMA-IR (P = 0.001) were significantly higher in diabetic patients compared with non-diabetic subjects. Levels of malondialdehyde (MDA) and carbonyl content were higher in the diabetes group. Conversely, total thiol content, and ferric reduction of plasma was higher in the healthy group. The mRNA levels of Nrf2 were negatively correlated with Keap1 and IL-6 gene expression. We observed a significant positive correlation between mRNA levels of Chop1, Grp78, and Nrf2 transcription levels. Conclusion: The data of the present study suggest that the impaired function of the Nrf2/Keap1 system is associated with pathological factors such as ER stress and inflammation.