Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

American Journal of Nephrology, Journal Year: 2017, Volume and Issue: 45(6), P. 473 - 483

Published: Jan. 1, 2017

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

Language: Английский

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 18(4), P. 295 - 317

Published: Jan. 4, 2019

Language: Английский

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Mitochondrial energetics in the kidney

Nature Reviews Nephrology, Journal Year: 2017, Volume and Issue: 13(10), P. 629 - 646

Published: Aug. 14, 2017

Language: Английский

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Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease

New England Journal of Medicine, Journal Year: 2013, Volume and Issue: 369(26), P. 2492 - 2503

Published: Nov. 9, 2013

Although inhibitors of the renin-angiotensin-aldosterone system can slow progression diabetic kidney disease, residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related 2 activators further reduce this unknown.We randomly assigned 2185 patients with type diabetes mellitus and stage 4 chronic disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute 1.73 m(2) body-surface area) bardoxolone methyl, at a daily dose 20 mg, or placebo. The primary composite outcome was end-stage renal (ESRD) death from cardiovascular causes.The sponsor steering committee terminated trial on recommendation independent data safety monitoring committee; median follow-up 9 months. A total 69 1088 (6%) methyl 1097 placebo had (hazard ratio in group vs. group, 0.98; 95% confidence interval [CI], 0.70 1.37; P=0.92). In ESRD developed 43 patients, 27 died causes; 51 19 causes. 96 were hospitalized for heart failure failure, as compared 55 ratio, 1.83; CI, 1.32 2.55; P<0.001). Estimated GFR, blood pressure, urinary albumin-to-creatinine increased significantly body weight decreased group.Among did not higher events than prompted termination trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).

Language: Английский

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Diabetic Nephropathy: Challenges in Pathogenesis, Diagnosis, and Treatment

BioMed Research International, Journal Year: 2021, Volume and Issue: 2021, P. 1 - 17

Published: July 8, 2021

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Chronic hyperglycemia and high blood pressure are main risk factors for development DN. In general, screening microalbuminuria should be performed annually, starting 5 years after diagnosis in type 1 diabetes at annually thereafter 2 diabetes. Standard therapy glucose control using renin-angiotensin system blockade, targeting $\text{A}1\text{c}<7\%$ , <130/80 mmHg. Regression albuminuria remains an important therapeutic goal. However, there problems treatment nonproteinuric DN (NP-DN), which does not follow classic pattern fact, prevalence continues to increase, additional needed prevent or ameliorate condition. addition conventional therapies, vitamin D receptor activators, incretin-related drugs, therapies that target inflammation may also promising prevention progression. This review focuses on role oxidative stress pathogenesis DN, approaches NP-DN, current emerging interventions.

Language: Английский

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Expansion of Urease- and Uricase-Containing, Indole- and p-Cresol-Forming and Contraction of Short-Chain Fatty Acid-Producing Intestinal Microbiota in ESRD

American Journal of Nephrology, Journal Year: 2014, Volume and Issue: 39(3), P. 230 - 237

Published: Jan. 1, 2014

Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure function of microbiome. Recently, we found marked differences abundance numerous bacterial taxa between ESRD healthy individuals. Influx urea uric acid dietary restriction fruits vegetables to prevent hyperkalemia alter patients' intestinal milieu. We hypothesized relative abundances bacteria possessing urease, uricase, p-cresol- indole-producing enzymes increased, while containing converting fiber short-chain fatty acids (SCFA) reduced ESRD.Reference sets genes interest were compiled family, families showing differential 12 24 individuals enrolled our original study compiled. Overlap was assessed using hypergeometric distribution tests.Among 19 microbial dominant patients, possessed 5 4 indole p-cresol-forming enzymes. Among diminished 2 butyrate-forming Probabilities these overlapping distributions <0.05.ESRD patients exhibited significant expansion p-cresol forming enzymes, contraction Given deleterious effects indoxyl sulfate, urea-derived ammonia, beneficial actions SCFA, metabolism contribute uremic toxicity inflammation.

Language: Английский

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The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases

Aging and Disease, Journal Year: 2018, Volume and Issue: 10(3), P. 637 - 637

Published: Dec. 13, 2018

Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] their elimination by through protective mechanisms, including (antioxidants). This Such leads to damage cells important biomolecules cells, with hence posing a potential adverse impact on the whole organism. At center day-to-day biological response oxidative Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related 2 (Nrf2)- antioxidant elements (ARE) pathway, which regulates transcription many several genes that preserve cellular homeostasis detoxification process eliminate carcinogens toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays key role in maintenance under stress, inflammatory, carcinogenic, pro-apoptotic conditions, allows us consider it pharmacological target. Herein, we review discuss recent advancements regulation system, its physiological pathophysiological e.g. such exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver kidney etc. such.

Language: Английский

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Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives

Cells, Journal Year: 2022, Volume and Issue: 11(3), P. 552 - 552

Published: Feb. 5, 2022

Reactive oxygen and nitrogen species (RONS) are generated through various endogenous exogenous processes; however, they neutralized by enzymatic non-enzymatic antioxidants. An imbalance between the generation neutralization of oxidants results in progression to oxidative stress (OS), which turn gives rise diseases, disorders aging. The characteristics aging include progressive loss function tissues organs. theory explains that age-related functional losses due accumulation reactive (ROS), their subsequent damages tissue deformities. Moreover, diseases caused OS cardiovascular [CVDs], chronic obstructive pulmonary disease, kidney neurodegenerative cancer. OS, induced ROS, is different antioxidants prevents cells, organs from damage. However, prolonged decreases content antioxidant status cells reducing activities reductants antioxidative enzymes pathological conditions. Therefore, aim present review discuss mechanism ROS-induced signaling age-associated complications mediated toxic manifestations order devise effective preventive curative natural therapeutic remedies.

Language: Английский

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Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome

Journal of Immunology Research, Journal Year: 2018, Volume and Issue: 2018, P. 1 - 16

Published: Sept. 6, 2018

Persistent, low-grade inflammation is now considered a hallmark feature of chronic kidney disease (CKD), being involved in the development all-cause mortality these patients. Although substantial improvements have been made clinical care, CKD remains major public health burden, affecting 10-15% population, and its prevalence constantly growing. Due to insidious nature, rarely diagnosed early stages, once developed, progression unfortunately irreversible. There are many factors that contribute setting inflammatory status CKD, including increased production proinflammatory cytokines, oxidative stress acidosis, recurrent infections, altered metabolism adipose tissue, last but not least, gut microbiota dysbiosis, an underestimated source microinflammation. In this scenario, huge step forward was by increasing omics approaches, specially designed for identification biomarkers useful diagnostic follow-up. Recent advances could provide novel insights deciphering pathophysiology; thus, circulating biomarker panels using state-of-the-art proteomic technologies improve diagnosis, monitoring, prognostics. This review aims summarize recent knowledge regarding relationship between highlighting current as well inflammasomes dysbiosis involvement culminating with troubling bidirectional connection renal malignancy, raised on background condition.

Language: Английский

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Diabetic nephropathy &ndash; complications and treatment

International Journal of Nephrology and Renovascular Disease, Journal Year: 2014, Volume and Issue: unknown, P. 361 - 361

Published: Oct. 1, 2014

Abstract: Diabetic nephropathy is a significant cause of chronic kidney disease and end-stage renal failure globally. Much research has been conducted in both basic science clinical therapeutics, which enhanced understanding the pathophysiology diabetic expanded potential therapies available. This review will examine current concepts management context some aspects relevant to approaches taken novel, investigative treatment strategies. Keywords: diabetes, nephropathy, albuminuria, disease, inflammation

Language: Английский

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