Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease

Oxidative stress and inflammation are mediators in the development and progression of chronic kidney disease (CKD) and its complications, and they are inseparably linked as each begets and amplifies the other. CKD-associated oxidative stress is due to increased production of reactive oxygen species (ROS) and diminished antioxidant capacity. The latter is largely caused by impaired activation of Nrf2, the transcription factor that regulates genes encoding antioxidant and detoxifying molecules. Protective effects of Nrf2 are evidenced by amelioration of oxidative stress, inflammation, and kidney disease in response to natural Nrf2 activators in animal models, while Nrf2 deletion amplifies these pathogenic pathways and leads to autoimmune nephritis. Given the role of impaired Nrf2 activity in CKD-induced oxidative stress and inflammation, interventions aimed at restoring Nrf2 may be effective in retarding CKD progression. Clinical trials of the potent Nrf2 activator bardoxolone methyl showed significant improvement in renal function in CKD patients with type 2 diabetes. However, due to unforeseen complications the BEACON trial, which was designed to investigate the effect of this drug on time to end-stage renal disease or cardiovascular death in patients with advanced CKD, was prematurely terminated. This article provides an overview of the role of impaired Nrf2 activity in the pathogenesis of CKD-associated oxidative stress and inflammation and the potential utility of targeting Nrf2 in the treatment of CKD. Oxidative stress and inflammation are mediators in the development and progression of chronic kidney disease (CKD) and its complications, and they are inseparably linked as each begets and amplifies the other. CKD-associated oxidative stress is due to increased production of reactive oxygen species (ROS) and diminished antioxidant capacity. The latter is largely caused by impaired activation of Nrf2, the transcription factor that regulates genes encoding antioxidant and detoxifying molecules. Protective effects of Nrf2 are evidenced by amelioration of oxidative stress, inflammation, and kidney disease in response to natural Nrf2 activators in animal models, while Nrf2 deletion amplifies these pathogenic pathways and leads to autoimmune nephritis. Given the role of impaired Nrf2 activity in CKD-induced oxidative stress and inflammation, interventions aimed at restoring Nrf2 may be effective in retarding CKD progression. Clinical trials of the potent Nrf2 activator bardoxolone methyl showed significant improvement in renal function in CKD patients with type 2 diabetes. However, due to unforeseen complications the BEACON trial, which was designed to investigate the effect of this drug on time to end-stage renal disease or cardiovascular death in patients with advanced CKD, was prematurely terminated. This article provides an overview of the role of impaired Nrf2 activity in the pathogenesis of CKD-associated oxidative stress and inflammation and the potential utility of targeting Nrf2 in the treatment of CKD. Oxidative stress and inflammation are features of chronic kidney disease (CKD) and drivers of CKD progression, as well as of its cardiovascular and other complications.1.Himmelfarb J. Hakim R.M. Oxidative stress in uremia.Curr Opin Nephrol Hypertens. 2003; 12: 593-598Crossref PubMed Scopus (110) Google Scholar, 2.Himmelfarb J. Stenvinkel P. Ikizler T.A. et al.The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia.Kidney Int. 2002; 62: 1524-1538Abstract Full Text Full Text PDF PubMed Scopus (701) Google Scholar, 3.Vaziri N.D. Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension.Curr Opin Nephrol Hypertens. 2004; 13: 93-99Crossref PubMed Scopus (154) Google Scholar, 4.Vaziri N.D. 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Clinical review: oxygen as a signaling molecule.Crit Care. 2010; 14: 234Crossref PubMed Scopus (32) Google Scholar Besides mitochondria, a number of cytosolic enzymes, including oxygenases, oxidases, and peroxidases, generate O2•- and H2O2. Although uncontained H2O2 and superoxide can cause oxidative stress and cytotoxicity, when produced at a normal rate, the healthy organism is well equipped to neutralize them.7.Rosenthal J. Nocera D.G. Role of proton-coupled electron transfer in O-O bond activation.Acc Chem Res. 2007; 40: 543-553Crossref PubMed Scopus (0) Google Scholar,9.Bartz R.R. Piantadosi C.A. Clinical review: oxygen as a signaling molecule.Crit Care. 2010; 14: 234Crossref PubMed Scopus (32) Google Scholar For example, O2•- is transformed into H2O2 (2O2•-+2H→ H2O2) by the superoxide dismutase (SOD) family of enzymes, which are present in the mitochondria (Mn-SOD), cytoplasm (Cu,Zn-SOD), and plasma membrane (EC-SOD). Similarly, H2O2 is converted to water by catalase and glutathione peroxidase. Accordingly, the ability of superoxide and H2O2 to directly cause oxidative stress and tissue injury is limited. As a matter of fact, under normal conditions they serve as signaling molecules or second messengers for various growth factors and hormones. However, under pathological conditions, they can serve as substrates for the generation of highly reactive and cytotoxic products that the organism is not equipped to contain. These include production of the following: hydroxyl radical (•OH) from H2O2 in the presence of transition metals, such as catalytically active iron (H2O2+Fe2+→•OH+OH-+ Fe3+); peroxynitrite from superoxide in the presence of nitric oxide (NO+O2• →ONOO-); and hypochlorous acid (HOCl), commonly known as bleach, from H2O2 in the presence of myeloperoxidase (H2O2+Cl-→HOCl) (Figure 1). Generation of these highly reactive and cytotoxic secondary molecules mediates the pathological changes involved in many diverse progressive and degenerative disorders.7.Rosenthal J. Nocera D.G. Role of proton-coupled electron transfer in O-O bond activation.Acc Chem Res. 2007; 40: 543-553Crossref PubMed Scopus (0) Google Scholar,9.Bartz R.R. Piantadosi C.A. Clinical review: oxygen as a signaling molecule.Crit Care. 2010; 14: 234Crossref PubMed Scopus (32) Google Scholar Under normal conditions, ROS produced during metabolism are contained by the natural antioxidant defense system. However, when ROS production exceeds the capacity of this system, it leads to oxidative stress in which the uncontained or uncontainable ROS cause tissue damage and dysfunction by attacking, denaturing, and modifying structural and functional molecules and by activating redox-sensitive transcription factors and signal transduction pathways. These events result in necrosis, apoptosis, inflammation, fibrosis, and other disorders that participate in the disease process. Thus, oxidative stress occurs as a result of increased ROS production and/or an impaired antioxidant defense system. The natural antioxidant defense system consists of numerous ROS scavenger molecules of dietary and endogenous origin, antioxidant enzymes and substrates, and phase 2 detoxifying enzymes. Each component of this system provides a specific function and works in a highly coordinated manner with the other components to fulfill the task of protecting against tissue injury. Consequently, the components of this system are not interchangeable, and, as such, supernormal quantities of one do not compensate for a deficiency in the other(s).10.Gutteridge J.M. Halliwell B. Antioxidants: molecules, medicines, and myths.Biochem Biophys Res Commun. 2010; 393: 561-564Crossref PubMed Scopus (145) Google Scholar Nuclear factor-erythroid-2-related factor 2 (Nrf2) has a central role in the basal activity and coordinated induction of over 250 genes, including those encoding antioxidant and phase 2 detoxifying enzymes and related proteins, such as catalase, SOD, UDP-glucuronosyltransferase, NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, and thioredoxin.11.Li W. Khor T.O. Xu C. et al.Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.Biochem Pharmacol. 2008; 76: 1485-1489Crossref PubMed Scopus (202) Google Scholar,12.Wakabayashi N. Slocum S.L. 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In addition to modification of Keap1, nuclear translocation of Nrf2 may occur via phosphorylation of its threonine or serine residues by upstream kinases, such as protein kinase C, mitogen-activated protein kinases, phosphatidylinositol-3-kinase/Akt, casein kinase-2, and the endoplasmic reticulum enzyme PERK (protein kinase RNA-like endoplasmic reticulum kinase).16.Surh Y.J. Kundu J.K. Na H.K. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.Planta Med. 2008; 74: 1526-1539Crossref PubMed Scopus (345) Google Scholar,17.Cullinan S.B. Diehl J.A. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.J Biol Chem. 2004; 279: 20108-20117Crossref PubMed Scopus (250) Google Scholar Regulation of cellular antioxidant and anti-inflammatory machinery by Nrf2 has a central role in defense against oxidative stress.11.Li W. 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