|Nuclear factor (erythroid-derived 2)-like 2|
|RNA expression pattern|
Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor which in humans is encoded by the NFE2L2 gene. Nrf2 is a master regulator of the antioxidant response. The antioxidant response is important for the amelioration of oxidative stress. Oxidative stress can result in cancer, cardiovascular diseases, inflammation, neurological diseases, and renal disease. Because Nrf2 is able to induce genes important in combating oxidative stress, thereby activating the body’s own protective response, it is able to protect from a variety of [oxidative stress]-related complications , even in situations where the administration of exogenous antioxidants (such as Vitamin C and Vitamin E) have failed.
NFE2, NFE2L1, and NFE2L2 (this protein) comprise a family of human genes encoding basic leucine zipper (bZIP) transcription factors. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.
Under normal or unstressed conditions, Nrf2 is tethered in the cytoplasm by another protein call Kelch like-ECH-associated protein 1 (Keap1). Keap1 acts as a substrate adaptor protein for Cullin 3-based ubiquitination, which results in the [proteasomal] degradation of Nrf2, and under normal conditions Nrf2 has a half-life of only 20 minutes. Oxidative stress or electrophilic stress disrupts critical cysteine residues in Keap1, resulting in a disruption of the Keap1-Cul3 ubitquitination system and a build-up of Nrf2 in the cytoplasm. Unbound Nrf2 is then able to translocate into the nucleus, where it will heterodimerize with a small Maf protein and bind to the Antioxidant Response Element (ARE) in the upstream promoter region of many antioxidative genes, where it will initiate their transcription. The coordinated effort of the induction of the many Nrf2 target genes has a profound impact on combating oxidative stress, inflammation, and thus, disease. Nrf2 upregulates its own expression by binding to an Antioxidant Response Element (ARE) sequence in its promoter region.
Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:
Nrf2 possesses six highly conserved domains called Nrf2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf proteins. The Neh2 domain allows for binding of Nrf2 to its cytosolic repressor Keap1. The Neh3 domain may play a role in Nrf2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus. The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP [Response Element Binding Protein] (CBP), which possesses intrinsic [histone acetyltransferase] activity. Finally, the Neh6 domain may contain a degron that is involved in the degradation of Nrf2, even in stressed cells, where the half-life of Nrf2 protein is longer than in unstressed conditions.
Nrf2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.
In recent years, Nrf2 has become an area of intense research (See Figure). A common theme in most of this research is that activation of Nrf2 upregulates a coordinated antioxidant response and is therefore, capable of protecting in a wide variety of animal models of [oxidative stress]-related injury and inflammatory disease. Therefore, Nrf2 represents a novel drug target. The diseases that could be treated or prevented by Nrf2 activation seem extensive as most have an etiology in oxidative stress.
Some Nrf2 activators have been given to humans in clinical trials. The [dithiolethiones] are a class of organosulfur compounds, of which, [oltipraz] is the most well-studied. Oltirpraz has been shown to inhibit cancer formation in a variety of rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. However, clinical trials involving oltipraz have demonstrated significant side effects with no or questionable chemopreventive efficacy. In one clinical study, side effects after 8 weeks of treatment included numbness, tingling, and pain in the extremities. In another study, side effects after 4 weeks included gastrointestinal toxicity. Oltipraz has also been shown to generate [superoxide] radical, which can be quite toxic.
A series of synthetic oleane triterpenoid compounds that are Nrf2 activators and referred to as Antioxidant Inflammatory Modulators (AIMs), are in clinical development at Reata Pharmaceuticals. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), is currently in phase II clinical trials for the treatment of chronic kidney disease (CKD) in patients with diabetes mellitus. It has been established that there is a clear relationship between oxidative stress and inflammation and the various pathologies associated with diabetes, including diabetic nephropathy and chronic kidney disease. Therefore, Nrf2 represents a very novel target for the treatment of CKD. In fact, a recent presentation of data from a Phase 2a trial of bardoxolone methyl indicated that this novel agent produced a dose and time-dependent improvement in kidney function (eGFR) as well as measures of diabetes and cardiovascular risk.[24 ] Reata also indicates that it has other Nrf2 inducers in the same class that are in preclinical development for the treatment of CNS and respiratory diseases, which also have been shown to have causality from oxidative stress.