Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is a novel therapeutic target for diabetic complications

Abstract

Diabetes is a leading cause of death and disability. In 2004, 3.4 million people worldwide died of symptoms relating to high blood sugar. Diabetic complications are caused by organ damage resulting from long-term exposure to high blood sugar, and include diseases such as heart failure, kidney failure, vision loss and neuropathy. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, also known as NRF2) is an important component of the intracellular antioxidant machinery and a target for treatment of diabetic complications. This article reviews the role of NFE2L2 in diabetic complications with a focus on diabetic nephropathy, cardiomyopathy, neuropathy and retinopathy. Activation of NFE2L2 protects against oxidative stress in vitro and in vivo, and represents an important target for prophylaxis and treatment of diabetic complications. NFE2L2 has potential clinical applications for diabetic patients in the near future.

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

“…Upon oxidative stress, Nrf2 escapes Kelch-like ECH-associated protein 1 (Keap1)-mediated repression, translocates to the nucleus, binds to antioxidant response element, and induces the expression of a battery of antioxidant proteins, one of the most important of which is heme oxygenase 1 (HO-1) (4). Nrf2 has emerged as an important target in diabetes and related complications (5,6), and low-dose dh404, which is an analog of the Nrf2 agonist bardoxolone methyl, lowers oxidative stress and protects against diabetes-associated atherosclerosis (7). These studies suggest that augmentation of antioxidant defenses via upregulation of the Nrf2 pathway may be a novel target for the prevention and treatment of diabetic complications.…”

Therapeutic potential of pterostilbene against pancreatic beta‐cell apoptosis mediated through Nrf2

“…The coordinated up‐regulation of genes coding for detoxifying enzymes, antioxidant enzymes and anti‐inflammatory regulators has been shown to be a potential therapeutic strategy against inflammation and oxidative stress‐induced pancreatic beta‐cell damage (Rodgers et al ., ; Hernandez‐Alvarez et al ., ; Kume et al ., ; Xu et al ., ). The transcription factor Nrf2 (nuclear factor erythroid 2‐related factor 2) regulates important cellular defence mechanisms that manage chemical and oxidative stress (Itoh et al ., ; Kensler et al ., ); these include intracellular antioxidants, phase II detoxifying enzymes and proteins involved in detoxifying xenobiotics and neutralizing reactive oxygen species (ROS) to promote cell survival and maintain cellular redox homeostasis (Zhang, ; Lau et al ., ).…”

Effect of plant extracts on H2O2-induced inflammatory gene expression in macrophages

“…EA and ES, as well as AL, CS, PG, and VM, upregulated NFE2L2 , a transcriptional regulator of antioxidant enzymes with an important role in attenuating oxidative stress associated with diseases 71. CS has been shown to activate NFE2L2 in HL-1 murine cardiomyocytes and to induce phase II enzymes through the antioxidant response element and concomitant protection against H 2 O 2 72.…”