scholarly journals Pharmacotherapy against Oxidative Stress in Chronic Kidney Disease: Promising Small Molecule Natural Products Targeting Nrf2-HO-1 Signaling

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 258
Author(s):  
Md Jamal Uddin ◽  
Ee Hyun Kim ◽  
Md. Abdul Hannan ◽  
Hunjoo Ha
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Natural Products ◽  
Kidney Disease ◽  
Small Molecule ◽  
Kidney Diseases ◽  
Critical Role ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Major Health Problem

The global burden of chronic kidney disease (CKD) intertwined with cardiovascular disease has become a major health problem. Oxidative stress (OS) plays an important role in the pathophysiology of CKD. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) antioxidant system plays a critical role in kidney protection by regulating antioxidants during OS. Heme oxygenase-1 (HO-1), one of the targets of Nrf2-ARE, plays an important role in regulating OS and is protective in a variety of human and animal models of kidney disease. Thus, activation of Nrf2-HO-1 signaling may offer a potential approach to the design of novel therapeutic agents for kidney diseases. In this review, we have discussed the association between OS and the pathogenesis of CKD. We propose Nrf2-HO-1 signaling-mediated cell survival systems be explored as pharmacological targets for the treatment of CKD and have reviewed the literature on the beneficial effects of small molecule natural products that may provide protection against CKD.

scholarly journals Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis

2013 ◽  
Vol 4 (11) ◽  
pp. e921-e921 ◽  
Author(s):  
S Tanigawa ◽  
C H Lee ◽  
C S Lin ◽  
C C Ku ◽  
H Hasegawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcriptional Activation ◽  
Leucine Zipper ◽  
Target Genes ◽  
Critical Role ◽  
Notch Receptor ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mobility Shift ◽  
Basic Leucine Zipper

Abstract Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.

scholarly journals Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

2017 ◽  
Vol 45 (6) ◽  
pp. 473-483 ◽  
Author(s):  
Masahiro Nezu ◽  
Norio Suzuki ◽  
Masayuki Yamamoto
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Related Factor ◽  
Renal Tubules ◽  
Renal Protection ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Basic Studies

Background: Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor for the antioxidative stress response and it activates a variety of cytoprotective genes related to redox and detoxification. NRF2 activity is regulated by the oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation of NRF2 through ubiquitinating NRF2 under unstressed conditions. Because oxidative stress is a major pathogenic and aggravating factor for kidney diseases, the KEAP1-NRF2 system has been proposed to be a therapeutic target for renal protection. Summary: Oxidative-stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models for acute kidney injury (AKI), in which NRF2 is transiently and slightly activated. Genetic or pharmacological enhancement of NRF2 activity in the renal tubules significantly ameliorates damage related to AKI and prevents AKI progression to chronic kidney disease (CKD) by reducing oxidative stress. These beneficial effects of NRF2 activation highlight the KEAP1-NRF2 system as an important target for kidney disease treatment. However, a phase-3 clinical trial of a KEAP1 inhibitor for patients with stage 4 CKD and type-2 diabetes mellitus (T2DM) was terminated due to the occurrence of cardiovascular events. Because recent basic studies have accumulated positive effects of KEAP1 inhibitors in moderate stages of CKD, phase-2 trials have been restarted. The data from the ongoing projects demonstrate that a KEAP1 inhibitor improves the glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns. Key Message: The KEAP1-NRF2 system is one of the most promising therapeutic targets for kidney disease, and KEAP1 inhibitors could be part of critical therapies for kidney disease.

scholarly journals Hippuric Acid Promotes Renal Fibrosis by Disrupting Redox Homeostasis via Facilitation of NRF2–KEAP1–CUL3 Interactions in Chronic Kidney Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 783
Author(s):  
Bowen Sun ◽  
Xifan Wang ◽  
Xiaoxue Liu ◽  
Longjiao Wang ◽  
Fazheng Ren ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Hippuric Acid ◽  
Redox Homeostasis ◽  
Pathological Process ◽  
Related Factor ◽  
Kidney Fibrosis ◽  
Nrf2 Activator

Chronic kidney disease (CKD) is characterized by the accumulation of protein-bound uremic toxins (PBUTs), which play a pathophysiological role in renal fibrosis (a common pathological process resulting in CKD progression). Accumulation of the PBUT hippuric acid (HA) is positively correlated with disease progression in CKD patients, suggesting that HA may promote renal fibrosis. Oxidative stress is the most important factor affecting PBUTs nephrotoxicity. Herein, we assessed the ability of HA to promote kidney fibrosis by disrupting redox homeostasis. In HK-2 cells, HA increased fibrosis-related gene expression, extracellular matrix imbalance, and oxidative stress. Additionally, reactive oxygen species (ROS)-mediated TGFβ/SMAD signaling contributed to HA-induced fibrotic responses. HA disrupted antioxidant networks by decreasing the levels of nuclear factor erythroid 2-related factor 2 (NRF2), leading to ROS accumulation and fibrotic responses, as evidenced by NRF2 activation and knockdown. Moreover, NRF2 levels were reduced by NRF2 ubiquitination, which was regulated via increased interactions of Kelch-like ECH-associated protein 1 with Cullin 3 and NRF2. Finally, renal fibrosis and redox imbalance promoted by HA were confirmed in rats. Importantly, sulforaphane (NRF2 activator) reversed HA-promoted renal fibrosis. Thus, HA promotes renal fibrosis in CKD by disrupting NRF2-driven antioxidant system, indicating that NRF2 is a potential therapeutic target for CKD.

Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: alterations, interventions, and relation to morbidity

2021 ◽  
Author(s):  
Christoffer Juul-Nielsen ◽  
Jianlin Shen ◽  
Peter Stenvinkel ◽  
Alexandra Scholze
Keyword(s):  
Gene Expression ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Inclusion Criteria ◽  
High Quality Research ◽  
System Components ◽  
Positive Correlations ◽  
Nrf2 Expression

Abstract Background NRF2 and its effectors NAD(P)H:quinoneoxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) are of interest in kidney disease. We therefore reviewed studies about their status in patients with chronic kidney disease (CKD). Methods We undertook systematic searches of PubMed and EMBASE databases. Alterations of NRF2, NQO1 and HO-1 in CKD, their responses to interventions and their relation to clinically relevant parameters were reported. Results We identified 1373 articles, of which 32 studies met the inclusion criteria. NRF2 levels were decreased in the majority of analyses of CKD patients. Half of the analyses showed a similar or increased NQO1 level vs. control, whereas NQO1 was decreased in half of the analyses. Most of the studies reported either an increased or similar HO-1 level in CKD patients compared to controls. For patients with CKD stages 1-4, studies reported positive correlations to markers of kidney disease severity. Also, positive associations of NQO1/HO-1 levels to inflammation and comorbidities were reported. One third of the studies showed discordant changes between gene expression and protein level of NRF2 system components. Two thirds of intervention studies (50% dietary, such as using resistant starch) reported an increase of NRF2, NQO1, or HO-1. Conclusions In patients with CKD, NRF2 expression was downregulated, while NQO1 and HO-1 showed varying alterations related to inflammation, comorbidities, and severity of kidney damage. Interventions that increased NRF2 system components were described, but their effectiveness and clinical relevance require further clinical studies of high quality. Research on gene expression together with protein analyses is indispensable to understand NRF2 system alterations in CKD.

scholarly journals Immunomodulatory Effects of Heme Oxygenase-1 in Kidney Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Yunlong Li ◽  
Kuai Ma ◽  
Zhongyu Han ◽  
Mingxuan Chi ◽  
Xiyalatu Sai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Heme Oxygenase ◽  
Cell Cycle Progression ◽  
Immune Cell ◽  
Kidney Diseases ◽  
General Term ◽  
New Drugs ◽  
Heme Oxygenase 1 ◽  
Multiple Processes

Kidney disease is a general term for heterogeneous damage that affects the function and the structure of the kidneys. The rising incidence of kidney diseases represents a considerable burden on the healthcare system, so the development of new drugs and the identification of novel therapeutic targets are urgently needed. The pathophysiology of kidney diseases is complex and involves multiple processes, including inflammation, autophagy, cell-cycle progression, and oxidative stress. Heme oxygenase-1 (HO-1), an enzyme involved in the process of heme degradation, has attracted widespread attention in recent years due to its cytoprotective properties. As an enzyme with known anti-oxidative functions, HO-1 plays an indispensable role in the regulation of oxidative stress and is involved in the pathogenesis of several kidney diseases. Moreover, current studies have revealed that HO-1 can affect cell proliferation, cell maturation, and other metabolic processes, thereby altering the function of immune cells. Many strategies, such as the administration of HO-1-overexpressing macrophages, use of phytochemicals, and carbon monoxide-based therapies, have been developed to target HO-1 in a variety of nephropathological animal models, indicating that HO-1 is a promising protein for the treatment of kidney diseases. Here, we briefly review the effects of HO-1 induction on specific immune cell populations with the aim of exploring the potential therapeutic roles of HO-1 and designing HO-1-based therapeutic strategies for the treatment of kidney diseases.

scholarly journals Molecular Mechanisms of Epigallocatechin-3-Gallate for Prevention of Chronic Kidney Disease and Renal Fibrosis: Preclinical Evidence

2019 ◽  
Vol 3 (9) ◽  
Author(s):  
Rattiyaporn Kanlaya ◽  
Visith Thongboonkerd
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Public Health Problem ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mesenchymal Transition

ABSTRACT Chronic kidney disease (CKD) is a common public health problem worldwide characterized by gradual decline of renal function over months/years accompanied by renal fibrosis and failure in tissue wound healing after sustained injury. Patients with CKD frequently present with profound signs/symptoms that require medical treatment, mostly culminating in hemodialysis and renal transplantation. To prevent CKD more efficiently, there is an urgent need for better understanding of the pathogenic mechanisms and molecular pathways of the disease pathogenesis and progression, and for developing novel therapeutic targets. Recently, several lines of evidence have shown that epigallocatechin-3-gallate (EGCG), an abundant phytochemical polyphenol derived from Camellia sinensis, might be a promising bioactive compound for prevention of CKD development/progression. This review summarizes current knowledge of molecular mechanisms underlying renoprotective roles of EGCG in CKD based on available preclinical evidence (from both in vitro and in vivo animal studies), particularly its antioxidant property through preservation of mitochondrial function and activation of Nrf2 (nuclear factor erythroid 2-related factor 2)/HO-1 (heme oxygenase-1) signaling, anti-inflammatory activity, and protective effect against epithelial mesenchymal transition. Finally, future perspectives, challenges, and concerns regarding its clinical use in CKD and renal fibrosis are discussed.

scholarly journals Rotenone Remarkably Attenuates Oxidative Stress, Inflammation, and Fibrosis in Chronic Obstructive Uropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ying Sun ◽  
Yue Zhang ◽  
Daqiang Zhao ◽  
Guixia Ding ◽  
Songming Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Complex I ◽  
Kidney Diseases ◽  
Heme Oxygenase 1 ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Collagen Iii ◽  
Kidney Morphology ◽  
Mitochondrial Complex I Inhibitor

Mitochondrial abnormality has been shown in many kidney disease models. However, its role in the pathogenesis of chronic kidney diseases (CKDs) is still uncertain. In present study, a mitochondrial complex I inhibitor rotenone was applied to the mice subjected to unilateral ureteral obstruction (UUO). Following 7-days rotenone treatment, a remarkable attenuation of tubular injury was detected by PAS staining. In line with the improvement of kidney morphology, rotenone remarkably blunted fibrotic response as shown by downregulation of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), collagen I, collagen III, andα-SMA, paralleled with a substantial decrease of TGF-β1. Meanwhile, the oxidative stress markers thiobarbituric acid-reactive substances (TBARS) and heme oxygenase 1 (HO-1) and inflammatory markers TNF-α, IL-1β, and ICAM-1 were markedly decreased. More importantly, the reduction of mitochondrial DNA copy number and mitochondrial NADH dehydrogenase subunit 1 (mtND1) expression in obstructed kidneys was moderately but significantly restored by rotenone, suggesting an amelioration of mitochondrial injury. Collectively, mitochondrial complex I inhibitor rotenone protected kidneys against obstructive injury possibly via inhibition of mitochondrial oxidative stress, inflammation, and fibrosis, suggesting an important role of mitochondrial dysfunction in the pathogenesis of obstructive kidney disease.

scholarly journals Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne’s Thread

2019 ◽  
Vol 20 (15) ◽  
pp. 3711 ◽  
Author(s):  
Anila Duni ◽  
Vassilios Liakopoulos ◽  
Stefanos Roumeliotis ◽  
Dimitrios Peschos ◽  
Evangelia Dounousi
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Critical Role ◽  
Cardiorenal Syndrome ◽  
Nuclear Factor Κb ◽  
Polycystic Kidney ◽  
Renal Autoregulation ◽  
Clinical Models ◽  
Vascular Oxidative Stress

Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein products produced during oxidative stress (advanced oxidation protein products—AOPPs) have been directly linked to podocyte damage, proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) as well as tubulointerstitial fibrosis. Vascular oxidative stress is considered to play a critical role in CKD progression, and ROS are potential mediators of the impaired myogenic responses of afferent renal arterioles in CKD and impaired renal autoregulation. Both oxidative stress and inflammation are CKD hallmarks. Oxidative stress promotes inflammation via formation of proinflammatory oxidized lipids or AOPPs, whereas activation of nuclear factor κB transcription factor in the pro-oxidant milieu promotes the expression of proinflammatory cytokines and recruitment of proinflammatory cells. Accumulating evidence implicates oxidative stress in various clinical models of CKD, including diabetic nephropathy, IgA nephropathy, polycystic kidney disease as well as the cardiorenal syndrome. The scope of this review is to tackle the issue of oxidative stress in CKD in a holistic manner so as to provide a future framework for potential interventions.

scholarly journals Perinatal Resveratrol Therapy Prevents Hypertension Programmed by Maternal Chronic Kidney Disease in Adult Male Offspring: Implications of the Gut Microbiome and Their Metabolites

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 567
Author(s):  
Chien-Ning Hsu ◽  
Chih-Yao Hou ◽  
Guo-Ping Chang-Chien ◽  
Sufan Lin ◽  
Hung-Wei Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Adult Male ◽  
Gut Microbiome ◽  
Critical Role ◽  
Male Offspring ◽  
Microbial Metabolites ◽  
Α Diversity

The gut microbiota plays a critical role in kidney disease and hypertension; however, whether maternal chronic kidney disease (CKD)-induced offspring hypertension is associated with alterations of the microbiota and microbial metabolites remains elusive. Using rat as an animal model, we conducted a maternal adenine-induced CKD model to examine whether adult male offspring develop hypertension and kidney disease. As resveratrol has antioxidant and prebiotic properties, we also aimed to elucidate whether its use in pregnancy and lactation can benefit hypertension programmed by maternal CKD via mediation of the gut microbiota and oxidative stress. Female Sprague-Dawley rats received regular chow (C) or chow supplemented with 0.5% adenine (CKD) from 3 weeks before pregnancy until lactation. One group of the adenine-induced CKD pregnant rats received resveratrol (R; 50 mg/L) in drinking water during gestation and lactation. Male offspring were divided into three groups: C, CKD, and CKD+R. The microbial metabolites analyzed were short chain fatty acids (SCFAs) in feces and trimethylamine (TMA)/trimethylamine N-oxide (TMAO) in plasma. We found perinatal resveratrol therapy protected against maternal CKD-induced hypertension in adult male offspring. The overall microbial compositions and diversity of bacterial community in the three groups were different. Resveratrol therapy increased α-diversity, decreased the Firmicutes to Bacteroidetes ratio, and increased the abundance of the genera Lactobacillus and Bifidobacterium. Perinatal resveratrol therapy increased plasma TMA levels but decreased the plasma TMAO-to-TMA ratio. Although resveratrol had negligible effect on fecal concentrations of SCFAs, it increased G-protein coupled receptor-41 (GPR41) protein levels in the offspring’s kidneys. Additionally, resveratrol therapy increased plasma levels of L-arginine and the L-arginine-to-ADMA ratio (AAR), and decreased oxidative stress. Overall, the protective effects of resveratrol against programmed hypertension are related to gut microbiome remodeling, including an increased abundance of beneficial microbes, mediation of the TMA-TMAO pathway, and alterations of SCFA receptors. Our results highlighted that targeting the microbiome and their metabolites might be potential therapeutic strategies to prevent maternal CKD-induced adverse pregnancy and offspring outcomes.

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