Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

Abstract

The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD.

Nrf2 Protein Serum Concentration in Human CKD Shows a Biphasic Behavior

“…Our analyses did not show a significant correlation between the inflammation marker C-reactive protein and Nrf2 protein concentration. The relationship between Nrf2 and inflammation is complex, with reported Nrf2 induction through inflammatory stimuli and Nrf2-mediated suppression of inflammation [ 4 , 39 ]. It might, therefore, not be possible to detect the relation between Nrf2 and inflammatory parameters in an organism by simple correlation analysis, as long as Nrf2-related mechanisms are an adequate response to stress conditions.…”

“…The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a central component in the regulation of cellular redox status and has gained considerable interest as a therapeutic target in many chronic diseases [ 1 , 2 ]. In chronic kidney disease (CKD), the Nrf2 system plays a crucial role in both CKD progression and the considerable CKD-related morbidity [ 3 , 4 ].…”

“…In human kidney disease, the Nrf2 system seems to display different functional states relating to the extent of kidney failure and comorbidities [ 3 , 4 , 8 ]. In kidney disease, endogenous activation and upregulation of the Nrf2 system related to oxidative stress and mild to moderately increased concentrations of the uremic toxin indoxyl sulfate have been described ([ 9 , 10 , 11 ], reviewed in [ 4 ]). Additionally, the uremic toxin methylglyoxal could contribute to an increase in Nrf2 protein concentration through Keap1 cross-linking [ 12 ].…”

Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients With Chronic Kidney Disease

“…For example, patients with advanced CKD display a reduction in NRF-2 (nuclear factor erythroid 2-related factor-2), a cellular protector from oxidative stress. 133 , 134 Inducing the NRF-2 pathway in endothelial cells could therefore be a novel therapeutic approach treating inflammatory diseases such as atherosclerosis by protecting the endothelium for oxidative damage as shown in. 135 …”

Transcription factor NRF2 as potential therapeutic target for preventing muscle wasting in aging chronic kidney disease patients

“…However, it is important to highlight that in CKD, strong activation (early nephropathy) or repression (advanced nephropathy) of endogenous NRF2 can be generated and depends on the cause, comorbidities, stage and duration of CKD, as well as on the accumulation of uremic toxins. Therefore, therapies targeting the NRF2 system will need to focus on a diversified approach that allows NRF2 to be increased or decreased according to homeostatic requirements [ 79 ].…”