Dataset Information

Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.

ABSTRACT:

Background

Obesity and type 2 diabetes mellitus (DM) contribute to a higher mortality rate in patients with septic acute kidney injury (AKI) during sepsis. Reactive oxygen species (ROS) is the major injury factor for sepsis. This study was aimed at exploring the potential therapeutic drug for septic AKI targeting on ROS.

Methods

A murine septic AKI model was established in both wild-type and high-fat diet-fed (HFD) mice. NADPH oxidase inhibitor Vas2870 was used in vivo to explore the role of NADPH oxidase in ROS release in septic AKI in diabetic mice. Ferrostatin-1 was administered to investigate the role of ferroptosis in ROS accumulation during NADPH oxidase activating in septic AKI in diabetic mice.

Results

Compared to chow diet-fed mice, HFD diabetic mice which were subjected to LPS exhibited aggravated renal function (blood urea nitrogen, creatinine clearance, and serum cystatin C) and oxidative stress (malondialdehyde, 4-HNE, ROS, 8-OHdG, and NADPH oxidase), thus resulting in a higher mortality rate. Septic renal injury was significantly attenuated by the ferroptosis inhibitor Fer-1 in HFD-challenged mice. Furthermore, ferroptosis accumulation and related protein expression (ASCL4, FTH1, and GPX4) were altered by LPS stimulation in HFD-challenged mice and suppressed by NADPH oxidase inhibition via Vas2870 in vivo. In summary, NADPH inhibition restored septic renal function from injury by suppressing ferroptosis accumulation in HFD-challenged mice.

Conclusion

These results suggest that targeting NADPH-mediated ROS release and ferroptosis accumulation is a novel therapeutic strategy to protect the kidney from septic injury in patients with obesity and type 2 DM.

SUBMITTER: Yao W

PROVIDER: S-EPMC8898803 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.

Yao Weifeng W Liao Haofeng H Pang Mengya M Pan Lijie L Guan Yu Y Huang Xiaolei X Hei Ziqing Z Luo Chenfang C Ge Mian M

Oxidative medicine and cellular longevity 20220227

<h4>Background</h4>Obesity and type 2 diabetes mellitus (DM) contribute to a higher mortality rate in patients with septic acute kidney injury (AKI) during sepsis. Reactive oxygen species (ROS) is the major injury factor for sepsis. This study was aimed at exploring the potential therapeutic drug for septic AKI targeting on ROS.<h4>Methods</h4>A murine septic AKI model was established in both wild-type and high-fat diet-fed (HFD) mice. NADPH oxidase inhibitor Vas2870 was used <i>in vivo</i> to e ...[more]

PMID: 35265258

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Project description:BackgroundDiabetic cardiomyopathy is a main cause of the increased morbidity in diabetic patients, no effective treatment is available so far. Polydatin, a resveratrol glucoside isolated from the Polygonum cuspidatum, was found by our and others have antioxidant and cardioprotective activities. Therapeutic effects of polydatin on diabetic cardiomyopathy and the possible mechanisms remains unclear. This study aimed to investigate the cardioprotective effects and underlying mechanisms of polydatin on myocardial injury induced by hyperglycemia.MethodsDiabetes in rats was made by high-fat diet combined with multiple low doses of streptozotocin, and then treated with polydatin (100 mg·kg-1·day-1, by gavage) for 8 weeks. Cardiac function was examined by echocardiography. Myocardial tissue and blood samples were collected for histology, protein and metabolic characteristics analysis. In cultured H9c2 cells with 30 mM of glucose, the direct effects of polydatin on myocyte injury were also observed.ResultsIn diabetic rats, polydatin administration significantly improved myocardial dysfunction and attenuated histological abnormalities, as evidenced by elevating left ventricular shortening fraction and ejection fraction, as well as reducing cardiac hypertrophy and interstitial fibrosis. In cultured H9c2 cells, pretreatment of polydatin dose-dependently inhibited high glucose-induced cardiomyocyte injury. Further observation evidenced that polydatin suppressed the increase in the reactive oxygen species levels, NADPH oxidase activity and inflammatory cytokines production induced by hyperglycemia in vivo and in vitro. Polydatin also prevented the increase expression of NOX4, NOX2 and NF-κB in the high glucose -stimulated H9c2 cells and diabetic hearts.ConclusionsOur results demonstrate that the cardioprotective effect of polydatin against hyperglycemia-induced myocardial injury is mediated by inhibition of NADPH oxidase and NF-κB activity. The findings may provide a novel understanding the mechanisms of the polydatin to be a potential treatment of diabetic cardiomyopathy.

Dataset Information

Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.

Background

Methods

Results

Conclusion

Publications

Inhibition of the NADPH Oxidase Pathway Reduces Ferroptosis during Septic Renal Injury in Diabetic Mice.

Similar Datasets

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