Dataset Information

Association of Nuclear Factor Erythroid-2-Related Actor 2 Gene Polymorphisms with Diabetic Nephropathy in Chinese Patients.

ABSTRACT:

Aim

Nuclear factor erythroid-2-related factor 2 (NRF2) has emerged as a therapeutic target in many diseases. To explore this further, we evaluated the relationships between the -617C/A (rs6721961) polymorphisms within the NRF2 promoter and diabetic nephropathy (DN) in Chinese Han patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 883 subjects with T2DM (500 without and 383 with DN) were enrolled in this study. Multivariable linear regression models were carried out to assess the association of DN with the -617C/A (rs6721961) polymorphisms.

Results

The AA genotype frequencies in patients with DN were significantly lower than those in patients without DN (χ² = 8.04, p = 0.018). Multivariate logistic regression analyses showed that individuals with the AA genotype had a significantly lower risk for DN (OR 0.52; 95% CI 0.28, 0.94; p = 0.029) than those with the CC genotype. Moreover, AA carriers had a significantly lower risk of DN (OR 0.46; 95% CI 0.26, 0.82; p = 0.009) relative to those with the CC + CA genotype, even after adjusting for known DN risk factors.

Conclusion

Our study indicated that the -617C/A polymorphism within the NRF2 promoter was significantly associated with DN in Chinese Han patients with T2DM.

SUBMITTER: Wang J

PROVIDER: S-EPMC8039206 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Maternal diabetes induces neural tube defects, and oxidative stress is a causal factor for maternal diabetes-induced neural tube defects. The redox gene nuclear factor erythroid 2-related factor 2 is the master regulator of the cellular antioxidant system. OBJECTIVE:In this study, we aimed to determine whether maternal diabetes inhibits nuclear factor erythroid 2-related factor 2 expression and nuclear factor erythroid 2-related factor 2-controlled antioxidant genes through the redox-sensitive miR-27a. STUDY DESIGN:We used a well-established type 1 diabetic embryopathy mouse model induced by streptozotocin for our in vivo studies. Embryos at embryonic day 8.5 were harvested for analysis of nuclear factor erythroid 2-related factor 2, nuclear factor erythroid 2-related factor 2-controlled antioxidant genes, and miR-27a expression. To determine if mitigating oxidative stress inhibits the increase of miR-27a and the decrease of nuclear factor erythroid 2-related factor 2 expression, we induced diabetic embryopathy in superoxide dismutase 2 (mitochondrial-associated antioxidant gene)-overexpressing mice. This model exhibits reduced mitochondria reactive oxygen species even in the presence of hyperglycemia. To investigate the causal relationship between miR-27a and nuclear factor erythroid 2-related factor 2 in vitro, we examined C17.2 neural stem cells under normal and high-glucose conditions. RESULTS:We observed that the messenger RNA and protein levels of nuclear factor erythroid 2-related factor 2 were significantly decreased in embryos on embryonic day 8.5 from diabetic dams compared to those from nondiabetic dams. High-glucose also significantly decreased nuclear factor erythroid 2-related factor 2 expression in a dose- and time-dependent manner in cultured neural stem cells. Our data revealed that miR-27a was up-regulated in embryos on embryonic day 8.5 exposed to diabetes, and that high glucose increased miR-27a levels in a dose- and time-dependent manner in cultured neural stem cells. In addition, we found that a miR-27a inhibitor abrogated the inhibitory effect of high glucose on nuclear factor erythroid 2-related factor 2 expression, and a miR-27a mimic suppressed nuclear factor erythroid 2-related factor 2 expression in cultured neural stem cells. Furthermore, our data indicated that the nuclear factor erythroid 2-related factor 2-controlled antioxidant enzymes glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and glutathione S-transferase A1 were down-regulated by maternal diabetes in embryos on embryonic day 8.5 and high glucose in cultured neural stem cells. Inhibiting miR-27a restored expression of glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and glutathione S-transferase A1. Overexpressing superoxide dismutase 2 reversed the maternal diabetes-induced increase of miR-27a and suppression of nuclear factor erythroid 2-related factor 2 and nuclear factor erythroid 2-related factor 2-controlled antioxidant enzymes. CONCLUSION:Our study demonstrates that maternal diabetes-induced oxidative stress increases miR-27a, which, in turn, suppresses nuclear factor erythroid 2-related factor 2 and its responsive antioxidant enzymes, resulting in diabetic embryopathy.