Should We STOP Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptor Blockers in Advanced Kidney Disease?

˜The œNephron journals/Nephron journals, Journal Year: 2016, Volume and Issue: 133(3), P. 147 - 158

Published: Jan. 1, 2016

Chronic kidney disease (CKD) is a worldwide public health problem associated with high prevalence of cardiovascular (CVD) and impaired quality life. Previous research for preventing loss glomerular filtration rate (GFR) has focused on reducing blood pressure (BP) proteinuria. Angiotensin converting enzyme inhibitors (ACEi) angiotensin II receptor antagonists (ARB) are commonly used in patients early CKD, but their value advanced CKD (estimated GFR (eGFR) ≤30 ml/min/1.73 m2) unknown. There remains debate about the omission ACEi/ARB use association CVD or heart failure. Does potential gain eGFR cessation outweigh adverse outcomes? This paper reviews current literature that addresses this issue. Several controversies discussed. Although lowering BP reduces events, evidence suggests ACEi/ARBs not superior to other antihypertensive agents. no studies assessing benefits therapy risk reduction non-dialysis CKD. The STOP ACEi trial will strengthen base shed light merits dangers renal function outcomes.

Language: Английский

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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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The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis

Physiological Reviews, Journal Year: 2018, Volume and Issue: 98(3), P. 1169 - 1203

Published: May 2, 2018

The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative electrophilic stresses both exogenous endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor redox insults, whereas NRF2 is transcription that robustly transduces chemical signals to regulate battery cytoprotective genes. represses activity under quiescent conditions, liberated from KEAP1-mediated repression on exposure stresses. rapid inducibility response based derepression mechanism an important feature KEAP1-NRF2 system. Recent studies have unveiled complexities functional contributions defined its broader involvement in biological processes, including cell proliferation differentiation, well cytoprotection. In this review, we describe historical milestones initial characterization provide comprehensive overview molecular mechanisms governing functions NRF2, their roles physiology pathology. We also refer clinical significance prophylactic therapeutic target for various diseases, particularly aging-related disorders. believe controlled harnessing key healthy aging well-being humans.

Language: Английский

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Fibrosis — A Common Pathway to Organ Injury and Failure

New England Journal of Medicine, Journal Year: 2015, Volume and Issue: 372(12), P. 1138 - 1149

Published: March 18, 2015

Fibrosis is a consequence of the inflammatory response. When fibrotic tissue becomes excessive, it can have diverse pathophysiological effects on number organ systems. The mechanisms underlying fibrosis and approaches to therapy are reviewed.

Language: Английский

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The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Molecular and Cellular Biology, Journal Year: 2020, Volume and Issue: 40(13)

Published: April 14, 2020

The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates activity transcription factor NRF2 by targeting it for ubiquitination proteasome-dependent degradation. In stress, intricate molecular mechanism facilitated sensor cysteines within allows escape ubiquitination, accumulate cell, translocate nucleus, where can promote its antioxidant program. Recent advances have revealed that contains multiple stress sensors inactivation modalities, together allow diverse cellular inputs, from metabolites dysregulated autophagy, regulate activity. This integration system into signaling metabolic pathways places activation as a critical regulatory node in many disease phenotypes suggests pharmaceutical modulation NRF2's cytoprotective will be beneficial human health broad range noncommunicable diseases.

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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Molecular basis of the Keap1–Nrf2 system

Free Radical Biology and Medicine, Journal Year: 2015, Volume and Issue: 88, P. 93 - 100

Published: June 25, 2015

Language: Английский

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Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy

The Lancet, Journal Year: 2017, Volume and Issue: 390(10105), P. 1888 - 1917

Published: April 21, 2017

Language: Английский

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Chronic kidney disease

Nature Reviews Disease Primers, Journal Year: 2017, Volume and Issue: 3(1)

Published: Nov. 22, 2017

Language: Английский

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Oxidative stress in chronic kidney disease

Pediatric Nephrology, Journal Year: 2018, Volume and Issue: 34(6), P. 975 - 991

Published: Aug. 13, 2018

Language: Английский

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