Dimethyl fumarate ameliorates endotoxin-induced acute kidney injury against macrophage oxidative stress

Abstract

Background Characterized by macrophage infiltration, renal inflammation during septic acute kidney injury (AKI) reveals a ubiquitous human health problem. Unfortunately, effective therapies with limited side effects are still lacking. This study is aiming to elucidate the role of Dimethyl fumarate (DMF) in macrophages against oxidative stress of septic AKI. Methods Balb/c mice were gavaged by 50 mg/kg DMF then injected with 10 mg/kg LPS by i.p. We examined LPS-induced renal dysfunction and histological features in murine kidneys. Raw264.7 macrophage cells were also treated with DMF and then induced by LPS. The mitotracker staining was used to follow mitochondria integrity by confocal microscopy. Flow cytometry measured the production of ROS by DCF-HDA and the expression of iNOS. Western blot detected the expression of Nrf-2 and Sirt1. Co-IP measured the interaction between Sirt1 and Nrf-2. Confocal microscopy observed the colocalization of Sirt1 and Nrf-2 in LPS-treated Raw264.7 macrophage cells. Results DMF ameliorated murine LPS nephritis with reduced blood urea nitrogen and serum creatinine, as well as decreased the histological alterations compared to the normal control. DMF significantly inhibited the expression of iNOS and reduced the production of nitrite in Raw264.7 cells following LPS treatment. Our study also revealed the role of DMF in protecting against intracellular ROS accumulation and mitochondria dysfunction in LPS-induced nephritis. DMF facilitated colocalization and interaction between Sirt1 and Nrf-2 in LPS-treated cells. Conclusions This study showed that DMF alleviated LPS-induced nephritis, indicating protective effects of DMF on macrophage against oxidative stress induced by LPS potentially involving Nrf-2-mediated pathway.

Hispidulin Ameliorates Endotoxin-Induced Acute Kidney Injury in Mice

“…It has been shown that nuclear factor erythroid-2-related factor 2 (Nrf2) is a key transcription factor that modulates the expression of antioxidant enzymes, including catalase and SOD [ 56 ]. Previous studies have shown that Nrf2 activation can serve as a useful therapeutic approach for septic AKI [ 57 , 58 , 59 ]. Interestingly, hispidulin can activate Nrf2-dependent antioxidant systems to suppress oxidative stress [ 19 , 60 , 61 ].…”

Changes in aging-induced kidney dysfunction in mice based on a metabolomics analysis

“…Malate is an intermediate in the citric acid cycle, and increased malate activity has been reported in cisplatin-induced kidney dysfunction that may be a repair mechanism for malate ( 26 ). Fumarate is converted from succinic acid and, like other TCA cycle metabolites, its regulation in kidney disease appears to be dynamic ( 27 – 29 ). Pyruvate is a key mediator of aerobic and anaerobic energy metabolism.…”

Oxidative Stress Management in Cardiorenal Diseases: Focus on Novel Antidiabetic Agents, Finerenone, and Melatonin

“…Dimethyl fumarate, an example of this category, led to reduction in myocardial infarct size in animal models of myocardial ischemia/reperfusion injury and to prevention of atherosclerosis in apoE −/− mice [ 152 , 153 ]. This agent may ameliorate nephrotoxicity due to various causes in in vivo animal models [ 154 , 155 , 156 , 157 ]. Moving to Nox inhibition, the dual Nox1/4 inhibitor setanaxib (GKT137831) has been investigated in the experimental setting of doxorubicin-, angiotensin II-, and hypertension-induced cardiac remodeling, displaying cardioprotective effects based on antioxidant and antifibrotic action [ 158 , 159 , 160 ].…”