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Modulation of Nrf2 expression alters high glucose-induced oxidative stress and antioxidant gene expression in mouse
Hang Li1, Fuxu Wang, Lianshan Zhang
1Department of Histology and Embryology, Hebei Medical University, Shijiazhuang, China.
Abstract:
Reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic nephropathy. Nuclear factor erythroid 2-related factor 2 (Nrf2) can up-regulate the expression of antioxidant genes and protect cells from oxidative damage. The current study is aimed at examining the effect of modulation of Nrf2 expression on high glucose-induced oxidative stress and Nrf2-targeting antioxidant expression in mouse mesangial cells. In this study, mouse mesangial cells were transiently transfected with Nrf2-plasmid or the Nrf2-specific siRNA. The high glucose-induced intracellular ROS, malondialdehyde, cell proliferation, and TGF-β1 secretion were measured. The levels of Nrf2, heme oxygenase-1 (HO-1), γ-glutamylcysteine synthethase (γ-GCS) expression, and nuclear expression of Nrf2 in mouse mesangial cells were determined. We found that high glucose induced ROS and malondialdehyde generation in mouse mesangial cells. Induction of Nrf2 over-expression reduced the high glucose-induced ROS and malondialdehyde production, inhibited cell proliferation and TGF-β1 secretion, accompanied by up-regulating the expressions of HO-1 and γ-GCS in mouse mesangial cells. However, knockdown of Nrf2 expression displayed reverse effects in mouse mesangial cells. All these results indicated that Nrf2 and its downstream antioxidants, HO-1 and γ-GCS, are negative regulators of high glucose-induced ROS-related mouse mesangial cell dysfunction.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) protects against high glucose-induced damage in kidney cells. Modulating Nrf2 levels impacts oxidative stress and antioxidant gene expression, offering therapeutic potential for diabetic nephropathy.
Area of Science:
- Nephrology
- Molecular Biology
- Oxidative Stress Research
Background:
- Diabetic nephropathy pathogenesis involves reactive oxygen species (ROS).
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant responses.
- Nrf2 activation protects cells against oxidative damage.
Purpose of the Study:
- To investigate the role of Nrf2 modulation in high glucose-induced oxidative stress.
- To examine the effect of Nrf2 on antioxidant gene expression in mouse mesangial cells.
- To understand Nrf2's impact on cellular dysfunction in a diabetic nephropathy model.
Main Methods:
- Mouse mesangial cells were transfected with Nrf2-plasmid or Nrf2-specific siRNA.
- High glucose conditions were used to induce oxidative stress.
- Measurements included intracellular ROS, malondialdehyde, cell proliferation, TGF-β1 secretion, and Nrf2/HO-1/γ-GCS expression levels.
Main Results:
- High glucose increased ROS and malondialdehyde in mesangial cells.
- Nrf2 over-expression reduced ROS and malondialdehyde, inhibited proliferation and TGF-β1 secretion.
- Nrf2 up-regulated heme oxygenase-1 (HO-1) and γ-glutamylcysteine synthethase (γ-GCS) expression.
Conclusions:
- Nrf2 acts as a negative regulator of high glucose-induced oxidative stress and mesangial cell dysfunction.
- Nrf2's downstream antioxidants, HO-1 and γ-GCS, are crucial in this protective mechanism.
- Modulating Nrf2 offers a potential therapeutic strategy for diabetic nephropathy.
