Diabetic neuropathy: A NRF2 disease?

Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has multifarious action with its target genes having redox-regulating functions and being involved in inflammation control, proteostasis, autophagy, and metabolic pathways. Therefore, the genes controlled by NRF2 are involved in the pathogenesis of myriad diseases, such as cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, autoimmune disorders, and cancer. Amidst this large array of diseases, diabetic neuropathy (DN) occurs in half of patients diagnosed with diabetes and appears as an injury inflicted upon peripheral and autonomic nervous systems. As a complex effector factor, NRF2 has entered the spotlight during the search of new biomarkers and/or new therapy targets in DN. Due to the growing attention for NRF2 as a modulating factor in several diseases, including DN, this paper aims to update the recently discovered regulatory pathways of NRF2 in oxidative stress, inflammation and immunity. It presents the animal models that further facilitated the human studies in regard to NRF2 modulation and the possibilities of using NRF2 as DN biomarker and/or as target therapy.

Keywords: NRF2; biomarker; diabetic neuropathy; inflammation; therapy target.

FIGURE 1

Molecular pathways of NRF2 involvement in DN. Glucose (Glc) intake is increased in diabetes leading to increased oxidative stress at the neuron level. Acute hyperglycemia associates an increase in NRF2 that induces protein kinase RNA‐like endoplasmic reticulum kinase (PERK) and p300/cellular retinol binding (CRB)‐binding protein (P300/CREB) activation. Chronic hyperglycemia induces a decrease in NRF2 that activates protein‐kinase C (PKC), activates NF‐kB, mitogen‐activated protein kinase (MAPK), and glycogen synthase kinase‐3 (GSK‐3). The alteration increases oxidative stress and sustains inflammation contributing to the development of DN. DN, diabetic neuropathy; NF‐κB, nuclear factor‐κB; NRF2, nuclear factor erythroid 2‐related factor 2.

FIGURE 2

NRF2 molecular pathways. When the cell is under basal conditions, NRF2 levels are low because it is complexed with KEAP1 that leads to proteasomal degradation. When the cell is subjected to various stress conditions like metabolic deregulations, oxidative stress, oncogenic signals, gene mutations, and so on, NRF2 levels increase, because the KEAP1‐NRF2 complex is disrupted. Hence, NRF2 will accumulate in the nucleus, interacting with other transcription factors and cofactors (eg, small musculoaponeurotic fibrosarcoma proteins – sMAF) inducing the transcription of target genes and the translation of proteins with antioxidant, detoxification, metabolic, and inflammatory actions. NRF2 induces an autoregulatory loop inducing its own NFE2L2 mRNA. KEAP1, Kelch‐like‐ECH‐associated protein 1; NRF2, nuclear factor erythroid 2‐related factor 2; Ub, ubiquitin.