Effect of Redox Modulating NRF2 Activators on Chronic Kidney Disease

Choi, Byungjoo; Kang, Kyung-Shin; Kwak, Mi‐Kyoung

doi:10.3390/molecules190812727

Cited by 147 publications

(117 citation statements)

References 210 publications

(210 reference statements)

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“…NRF2 is a member of the cap 'n collar family of transcription factors that controls expression of genes conferring protection against oxidative and electrophilic stress (Baird and Dinkova-Kostova, 2011;Jaramillo and Zhang, 2013). Table 2 lists 27 transcripts from the microarray whose expression levels have been identified in the literature as regulated by NRF2 (Agyeman et al, 2012;Suzuki et al, 2013;Choi et al, 2014;Hayes and Dinkova-Kostova, 2014). We tested 15 of these by qRT-PCR and confirmed all as inducible by FdUrd (Table 2).…”

Section: Ros Levelsmentioning

confidence: 99%

“…Under normal circumstances, NRF2 is maintained at low levels within the cell, a status maintained by the transcription factor's TABLE 2 Identification of FUra-inducible NRF2 target genes by gene expression profiling NRF2 target genes identified in the whole genome microarray analysis (Supplemental Table 2) are listed. Classification of each gene as an NRF2 target is based upon the literature (Agyeman et al, 2012;Suzuki et al, 2013;Choi et al, 2014;Hayes and Dinkova-Kostova, 2014). The fold change represents the extent of induction by exposure to 10 mM FUra for 24 hours (see text).…”

Section: Ros Levelsmentioning

confidence: 99%

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Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites

Özer¹,

Barbour²,

Clinton³

et al. 2015

Mol Pharmacol

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Thymidylate synthase (TYMS; EC 2.1.1.15) catalyzes the reductive methylation of 2ʹ-deoxyuridine-5ʹ-monophosphate (dUMP) by N 5 ,N 10 -methyhlenetetrahydrofolate, forming dTMP for the maintenance of DNA replication and repair. Inhibitors of TYMS have been widely used in the treatment of neoplastic disease. A number of fluoropyrimidine and folate analogs have been developed that lead to inhibition of the enzyme, resulting in dTMP deficiency and cell death. In the current study, we have examined the role of oxidative stress in response to TYMS inhibitors. We observed that intracellular reactive oxygen species (ROS) concentrations are induced by these inhibitors and promote apoptosis. Activation of the enzyme NADPH oxidase (NOX), which catalyzes one-electron reduction of O 2 to generate superoxide (O 2 d2 ), is a significant source of increased ROS levels in drug-treated cells. However, gene expression profiling revealed a number of other redox-related genes that may contribute to ROS generation. TYMS inhibitors also induce a protective response, including activation of the transcription factor nuclear factor E2-related factor 2 (NRF2), a critical mediator of defense against oxidative and electrophilic stress. Our results show that exposure to TYMS inhibitors induces oxidative stress that leads to cell death, while simultaneously generating a protective response that may underlie resistance against such death.

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Section: Ros Levelsmentioning

confidence: 99%

Section: Ros Levelsmentioning

confidence: 99%

Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites

Özer¹,

Barbour²,

Clinton³

et al. 2015

Mol Pharmacol

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show abstract

“…3). The relevance of Nrf2 in the pathogenesis of liver and kidney injury has emerged in diverse diet-induced models of NASH and CKD, where disease progression was accelerated by Nrf2 deletion and prevented by Nrf2 activators (75,76). On this basis, several natural and synthetic small-molecule Nrf2 activators are currently being evaluated in patients with NASH and CKD ( Table 2).…”

Section: Targeting Redox Regulation In the Pathogenesis Of Nafld And Ckdmentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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“…DCM is related to oxidative stress that is due to imbalance between ROS and/or reactive nitrogen species generation and their clearance by antioxidant defense systems [2][3][4][5][6]. Experimental and clinical studies have shown the important roles that Nrf2 and its downstream genes play in the pathogenesis of cardiac remodeling and heart failure induced by a number of factors.…”

Section: Implications Of Nrf2 Transcription Factor In Diabetic Complimentioning

confidence: 99%

“…Oxidative stress destroys critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. If Nrf2 is not ubiquitinated, it builds up in the cytoplasm and is translocated into the nucleus [4][5][6].…”

Section: Implications Of Nrf2 Transcription Factor In Diabetic Complimentioning

confidence: 99%