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

Weifeng Yao,Yu Guan,Haofeng Liao,Ziqing Hei,Xiaolei Huang,Mian Ge,Mengya Pang,Lijie Pan,Chenfang Luo,Liang-Jun Yan

doi:10.1155/2022/1193734

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.

Highlights

Diabetes mellitus (DM) is a prevalent global health problem that is one of the fastest growing emergencies of the 21st century, with approximately 10% morbidity [1]
From the second week of high-fat diet-fed (HFD) intervention, a significant increase in body weight was observed in the HFD group (p < 0:01), which persisted until the end of intervention (Figure 1(a))
We found that the cell membrane was broken and vacuolated, mitochondrial spine was decreased or absent, and membrane density was increased under LPS stimulation, which was deteriorated in high-fat diet- (HFD-)challenged mice

Summary

Introduction

Diabetes mellitus (DM) is a prevalent global health problem that is one of the fastest growing emergencies of the 21st century, with approximately 10% morbidity [1]. Obesity and type 2 diabetes mellitus (DM) contribute to a higher mortality rate in patients with septic acute kidney injury (AKI) during sepsis. Ferrostatin-1 was administered to investigate the role of ferroptosis in ROS accumulation during NADPH oxidase activating in septic AKI in diabetic mice. 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), resulting in a higher mortality rate. NADPH inhibition restored septic renal function from injury by suppressing ferroptosis accumulation in HFD-challenged mice. 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

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Conclusion