Oxidative Stress and NRF2/KEAP1/ARE Pathway in Diabetic Kidney Disease (DKD): New Perspectives.

Diabetes mellitus (DM) is one of the most debilitating chronic diseases worldwide, with increased prevalence and incidence. In addition to its macrovascular damage, through its microvascular complications, such as Diabetic Kidney Disease (DKD), DM further compounds the quality of life of these patients. Considering DKD is the main cause of end-stage renal disease (ESRD) in developed countries, extensive research is currently investigating the matrix of DKD pathophysiology. Hyperglycemia, inflammation and oxidative stress (OS) are the main mechanisms behind this disease. By generating pro-inflammatory factors (e.g., IL-1,6,18, TNF-α, TGF-ß, NF-κB, MCP-1, VCAM-1, ICAM-1) and the activation of diverse pathways (e.g., PKC, ROCK, AGE/RAGE, JAK-STAT), they promote a pro-oxidant state with impairment of the antioxidant system (NRF2/KEAP1/ARE pathway) and, finally, alterations in the renal filtration unit. Hitherto, a wide spectrum of pre-clinical and clinical studies shows the beneficial use of NRF2-inducing strategies, such as NRF2 activators (e.g., Bardoxolone methyl, Curcumin, Sulforaphane and their analogues), and other natural compounds with antioxidant properties in DKD treatment. However, limitations regarding the lack of larger clinical trials, solubility or delivery hamper their implementation for clinical use. Therefore, in this review, we will discuss DKD mechanisms, especially oxidative stress (OS) and NRF2/KEAP1/ARE involvement, while highlighting the potential of therapeutic approaches that target DKD via OS.

Study on the protective effect of quercetin on age-related macular degeneration in mice based on Nrf2/Keap1/ARE pathway / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To investigate the protective effect and mechanism of quercetin on age-related macular degeneration in mice through Nrf2/Keap1/ARE pathway. <p>METHODS: Kunming mice were used as research objects, which were divided into control group, model group and quercetin group. Fundus examination was showed whether yellow-white like glassy sputum substances appeared in the fundus of each group of mice; OCT was used to examine the retinal thickness of each group of mice; HE staining was used to observe the changes of retinal morphology in each group of mice; FFA was observed the fundus vascular integrity of each group of mice. The activities of SOD, GSH-Px, CAT and the contents of ROS and MDA in serum were detected by ELISA; Western blot was used to detect the expression of Nrf2/Keap1/ARE related proteins in the retina of each group. <p>RESULTS: Quercetin can reduce the yellow and white glassy wart substance in the fundus of mice and increase the thickness of the retina(<i>P</i><0.05), and the points of retinal vascular leakage is significantly reduced. Compared with the model group, the a-wave amplitude and b-wave amplitude of the quercetin group were significantly higher than those of the model group(<i>P</i><0.01); Quercetin can make the retinal structure of mice clearer, necrosis and shed part of the outer nuclear layer, and reduce the content of ROS and MDA in mouse serum(all <i>P</i><0.05), and increase the activities of SOD, GSH-Px, and CAT(all <i>P</i><0.05). Compared with the model group, the expression of Nrf2 protein in the retinal cytoplasm of mice in the quercetin group was up-regulated(<i>P</i><0.05), and the expression of Nrf2 protein in the nucleus was down-regulated(<i>P</i><0.05), GCL protein expression was down-regulated(<i>P</i><0.05).<p>CONCLUSION: Quercetin improved the oxidative stress state after retinal photodamage through the Nrf2/Keap1/ARE pathway, protected the retinal function, and protected against age-related macular degeneration.

Inhibition of autophagy reverses alcohol-induced hepatic stellate cells activation through activation of Nrf2-Keap1-ARE signaling pathway.

BACKGROUND: Numerous documents have indicated a critical role of autophagy in alcoholic liver fibrosis (ALF), but few papers have reported its function in hepatic stellate cells (HSCs) activation. The current study aimed to investigate the regulation effect of autophagy in HSCs activation, in further to explore the underlying mechanism involved. METHODS: HSC-T6 cells were treated with ethanol, 3-MA (autophagy inhibitor) or rapamycin (autophagy inducer), and cells were also transfected with si-Nrf2 or si-Keap1. Moreover, ALF animal model was established and Nrf-2(-/-), Keap1 (-/-) mice were purchased. The level of autophagy, the expression of α-SMA and CoL1A1, and Nrf2 antioxidant response were evaluated in stellate cells and livers. RESULTS: Ethanol treatment in cultured cells increased autophagy, oxidative stress level and promoted HSCs activation. Inhibition of autophagy reversed alcohol-induced HSCs activation and suppressed HSCs oxidative stress. Nrf2-Keap1-ARE pathway was involved in HSCs activation and oxidative stress regulated by autophagy. In addition, through in vivo study, we found that inhibition of autophagy could alleviate alcoholic fatty liver injury in ALF model mice and Nrf2 signaling was involved in autophagy regulated HSCs activation. CONCLUSION: These data implicated mechanisms underlying autophagy in regulating the fibrogenic response in HSCs activation.