Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Nezu, Masahiro; Suzuki, Norio; Yamamoto, Masayuki

doi:10.1159/000475890

Cited by 2,545 publications

(106 citation statements)

References 83 publications

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“…SCLT1 deficiency has been linked with cystic kidney 29 and SMAD genes (including SMAD3) have been reported to affect CKD progression when dysregulated 30 . INPP5B impairment has been associated with severe renal phenotypes, such as proximal tubule endocytosis 31 , while targeting NFE2L2 (NRF2) has been tested for prevention of Kidney Disease Progression 32 .…”

Section: Application Of Mantis-ml Predictions To Triage Results From mentioning

confidence: 99%

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

Vitsios

Petrovski

2019

Preprint

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Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses that result in candidate lists of genes. Often these analyses highlight several gene signals that might contribute to pathogenesis but are insufficiently powered to reach experiment-wide significance. This often triggers a process of laborious evaluation of highly-ranked genes through manual inspection of various public knowledge resources to triage those considered sufficiently interesting for deeper investigation. Here, we introduce a novel multi-dimensional, multi-step machine learning framework to objectively and more holistically assess biological relevance of genes to disease studies, by relying on a plethora of gene-associated annotations. We developed mantis-ml to serve as an automated machine learning (AutoML) framework, following a stochastic semisupervised learning approach to rank known and novel disease-associated genes through iterative training and prediction sessions of random balanced datasets across the protein-coding exome (n=18,626 genes). We applied this framework on a range of disease-specific areas and as a generic disease likelihood estimator, achieving an average Area Under Curve (AUC) prediction performance of 0.85. Critically, to demonstrate applied utility on exome-wide association studies, we overlapped mantis-ml disease-specific predictions with data from published cohort-level association studies. We retrieved statistically significant enrichment of high mantis-ml predictions among the top-ranked genes from hypothesis-free cohort-level statistics (p<0.05), suggesting the capture of true prioritisation signals. We believe that mantis-ml is a novel easy-to-use tool to support objectively triaging gene discovery and overall enhancing our understanding of complex genotype-phenotype associations.

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Section: Application Of Mantis-ml Predictions To Triage Results From mentioning

confidence: 99%

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

Vitsios

Petrovski

2019

Preprint

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“…Inflammatory cells, which are locally activated in the renal microenvironment or migrate from hematopoietic organs, further produce ROS. Thus, oxidative stress, as with inflammation, is regarded to be a key aggravating factor for the initiation and progression of AKI and CKD, including diabetic nephropathy, hypertension-associated kidney disease and toxic-induced nephropathy [18,20,24]. In these types of kidney disease, electrophiles accumulate as byproducts of impaired detoxification and abnormal metabolism and aggravate oxidative stress, making matters worse [25,26].…”

Section: Oxidative Stress In Kidneymentioning

confidence: 99%

“…To protect cells from harmful oxidative stress, the transcription factor Nrf2 plays an integrative role in inducing the expression of genes encoding enzymes involved in antioxidant (e.g., glutathione and NADPH) production and the reduction in pro-oxidants (e.g., heme and quinonoids, Figure 2) [14,18]. In unstressed cells, Nrf2 is constitutively synthesized but degraded by the Nrf2-specific ubiquitin ligase complex, in which the stress-sensor molecule Keap1 directly captures Nrf2 ( Figure 2).…”

Section: Role Of the Keap1-nrf2 System In Cytoprotection Against Oxidmentioning

confidence: 99%

“…Indeed, activators of Nrf2 (nuclear factor erythroid 2-related factor 2; a member of the Cap 'n' Collar [CNC] transcription factor family), which is the master regulator of antioxidant genes [13,14], are investigated in ongoing clinical trials as medicines for treating kidney disease [15][16][17]. The Nrf2 activators currently in development are compounds that inhibit Keap1 (Kelch-like ECH-associated protein 1), which negatively regulates Nrf2 under conditions free from oxidative stress [14,18]. In this review, we introduce the molecular functions of Keap1 and Nrf2 in kidney disease as well as up-to-date information on the development of drugs targeting the Keap1-Nrf2 system for kidney disease treatment.…”

Section: Introductionmentioning

confidence: 99%

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Roles of Nrf2 in Protecting the Kidney from Oxidative Damage

Nezu

Suzuki

2020

IJMS

Self Cite

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Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.

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“…Thus, the disturbance of redox homeostasis in the kidney endothelial compartment is likely to contribute to fibrogenesis as an intact endothelial function is considered indispensable for mounting an appropriate tissue repair response [62,63]. In the context of the antioxidant response the Keap1-Nrf2 system has been proposed to be a therapeutic target for renal protection [64]. Nrf2 is a key regulator of antioxidant defense system that modulates the expression of several genes in response to electrophilic stress including phase 2 response genes and antioxidant enzymes such as GCL [23,65].…”

Section: Espinosa-díez Et Almentioning

confidence: 99%

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

Espinosa

Miguel

Vallejo

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C TGlutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The ratelimiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH 4 . To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.

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Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Cited by 2,545 publications

References 83 publications

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

Stochastic semi-supervised learning to prioritise genes from high-throughput genomic screens

Roles of Nrf2 in Protecting the Kidney from Oxidative Damage

Role of Glutathione Biosynthesis in Endothelial Dysfunction and Fibrosis

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