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.

Keywords: CKD; NQO1; Nrf2; bardoxolone methyl; curcumin; fibrosis; hemodialysis; inflammation; kidney function; oxidative stress; redox signaling.

Figure 1

Nuclear factor erythroid 2-related factor 2. (A) In the OFF state, the nuclear factor erythroid 2-related factor 2 (Nrf2) is kept at a basal activity level by Kelch-like ECH-associated protein 1 (Keap1). In addition, the inhibition of Akt induces the upregulation of glycogen synthase kinase 3 beta (GSK3β), promoting the phosphorylation and degradation of Nrf2. Both mechanisms lead to Nrf2 degradation via the proteasome. (B) In the ON state, electrophiles and ROS modify the cysteine residues of Keap1, promoting its degradation via proteasome or via sequestosome (p62). The latter induces the nuclear translocation of Nrf2 to interact with the musculoaponeurotic fibrosarcoma (maf) proteins and bind to antioxidant response elements (AREs), triggering the expression of NADPH quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic (GCLC), and glutamate-cysteine ligase modifier (GCLM). The figure was created using BioRender.

Figure 2

The nuclear factor erythroid 2-related factor 2 (Nrf2) regulates inflammation in chronic kidney disease (CKD). (A) The activation of the renin-angiotensin system (RAS) augments ROS production. This ROS oxidizes the cysteine (Cys) groups of the nuclear factor-kappa B (NF-κB) inhibitor, IκB, modifying and promoting its proteasome degradation. This triggers the release of NF-κB, which competes with Nrf2 by the binding DNA site of CREB protein (CBP), (B) ROS overproduction also activates Nrf2, inducing its nuclear translocation. The latter upregulates heme oxygenase-1 (HO-1), avoiding NF-κB activation by impeding IκB phosphorylation. The figure was created using BioRender.

Figure 3

Differing scenarios for nuclear factor erythroid 2-related factor 2 (Nrf2) activation in renal fibrosis. (A) The downregulation of Nrf2 (↓Nrf2) induces the upregulation of the transcription growth factor-beta1 (↑TGF-β1), inducing fibrosis by promoting the production of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). In addition, ↓Nrf2 leads to the downregulation of catalase (↓catalase), upregulating the generation of angiotensinogen, which converts into angiotensin II (Ang II). Then, Ang II interacts with angiotensin receptor 1 (ATR1), upregulating the RAS pathway. Nrf2 downregulation also induces the decrease in heme oxygenase-1 (↓HO-1), promoting apoptosis and fibrosis. (B) In contrast, the upregulation of Nrf2 (↑Nrf2) induces fibrosis and hypertension. This mechanism is attributed to ROS overproduction, generated via advanced glycation end products (AGEs) by binding to its receptor (RAGE), which activates Nrf2. This mechanism induces Nrf2 translocation to the nucleus with the positioning in Ang/ACE promoter, which leads to fibrosis [38]. The figure was created using BioRender.

Figure 4

Nuclear factor erythroid 2-related factor 2 (Nrf2) activation and mitochondria. (A) Nrf2 upregulates fatty-acid catabolism via β-oxidation, a process occurring in the mitochondria by inducing the expression of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme in this mechanism. In contrast, Nrf2 inhibits acetyl-CoA carboxylase 1 (ACC1) via phosphorylation, preventing lipid biosynthesis. Furthermore, Nrf2 inhibits stearoyl-CoA desaturase. Nrf2 also induces the expression of the enzymes involved in the tricarboxylic-acid (TCA) cycle, upregulating this pathway. Nrf2 participates in mitochondria biogenesis by interacting with the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor 1 (NRF1), promoting the expression of transcription factor A, mitochondrial (TFAM). Moreover, NRF1 contains at least four binding sites for Nrf2, participating in antioxidant response. (B) Nrf2 overactivation might induce the overexpression of cluster of differentiation 36 (CD36), the principal receptor to fatty-acid uptake, leading to the accumulation of low-density lipoproteins (LDLs) in the cytosol. LDLs are lipids with a major propensity for oxidation, forming oxidized LDLs (oxLDLs), further damaging the mitochondria. Moreover, macrophages engulf oxLDLs, which causes macrophage foam-cell formation. Nrf2 upregulation also induces mitochondrial membrane potential, decreases respiratory capacity, and alters mitochondrial thiol protein groups, leading to the alteration of mitochondrial redox signaling pathways. The figure was created using BioRender.