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      Protective Role of Nrf2 in Renal Disease

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          Abstract

          Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases.

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          Most cited references278

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          Role of nrf2 in oxidative stress and toxicity.

          Qiang Ma (2013)
          Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.
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            Chronic Kidney Disease.

            The definition and classification of chronic kidney disease (CKD) have evolved over time, but current international guidelines define this condition as decreased kidney function shown by glomerular filtration rate (GFR) of less than 60 mL/min per 1·73 m(2), or markers of kidney damage, or both, of at least 3 months duration, regardless of the underlying cause. Diabetes and hypertension are the main causes of CKD in all high-income and middle-income countries, and also in many low-income countries. Incidence, prevalence, and progression of CKD also vary within countries by ethnicity and social determinants of health, possibly through epigenetic influence. Many people are asymptomatic or have non-specific symptoms such as lethargy, itch, or loss of appetite. Diagnosis is commonly made after chance findings from screening tests (urinary dipstick or blood tests), or when symptoms become severe. The best available indicator of overall kidney function is GFR, which is measured either via exogenous markers (eg, DTPA, iohexol), or estimated using equations. Presence of proteinuria is associated with increased risk of progression of CKD and death. Kidney biopsy samples can show definitive evidence of CKD, through common changes such as glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Complications include anaemia due to reduced production of erythropoietin by the kidney; reduced red blood cell survival and iron deficiency; and mineral bone disease caused by disturbed vitamin D, calcium, and phosphate metabolism. People with CKD are five to ten times more likely to die prematurely than they are to progress to end stage kidney disease. This increased risk of death rises exponentially as kidney function worsens and is largely attributable to death from cardiovascular disease, although cancer incidence and mortality are also increased. Health-related quality of life is substantially lower for people with CKD than for the general population, and falls as GFR declines. Interventions targeting specific symptoms, or aimed at supporting educational or lifestyle considerations, make a positive difference to people living with CKD. Inequity in access to services for this disease disproportionally affects disadvantaged populations, and health service provision to incentivise early intervention over provision of care only for advanced CKD is still evolving in many countries.
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              The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress.

              A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed.
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                Author and article information

                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                31 December 2020
                January 2021
                : 10
                : 1
                : 39
                Affiliations
                [1 ]Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, 14004 Cordoba, Spain; mel10anie@ 123456gmail.com (M.G.-H.); srayego@ 123456quironsalud.es (S.R.-M.); crisgcomplutense@ 123456gmail.com (C.G.-C.); biomorgui@ 123456hotmail.com (J.L.M.-P.)
                [2 ]Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Autónoma University, 28040 Madrid, Spain; cvazqu01@ 123456ucm.es (C.V.-C.); lucasopazo78@ 123456gmail.com (L.O.-R.); carmen.herencia@ 123456quironsalud.es (C.H.); smas@ 123456fjd.es (S.M.); aortiz@ 123456fjd.es (A.O.); jegido@ 123456fjd.es (J.E.)
                [3 ]Research Unit, Hospital Universitario Santa Cristina, IIS-Hospital Universitario de la Princesa, 28006 Madrid, Spain; alejandra.palominoantolin@ 123456gmail.com (A.P.-A.); javier.egea@ 123456inv.uam.es (J.E.)
                [4 ]Departament of Pharmacology and Therapeutics, Medicine Faculty, Instituto Teófilo Hernando, Autónoma University, 28029 Madrid, Spain
                [5 ]Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
                [6 ]Red Nacional Investigaciones Nefrológicas (REDINREN), 28040 Madrid, Spain
                [7 ]Weill Center for Metabolic Health and Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; arubionavarro@ 123456gmail.com
                [8 ]Department of Cell Biology, Physiology, and Immunology, Agrifood Campus of International Excellence (ceiA3), University of Cordoba, 14014 Cordoba, Spain; jmvillalba@ 123456uco.es
                [9 ]Hospital Universitario Reina Sofia, 14004 Cordoba, Spain
                [10 ]Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), 28040 Madrid, Spain
                Author notes
                [* ]Correspondence: juan.moreno@ 123456uco.es ; Tel.: +34-957-218-039
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-3586-3319
                https://orcid.org/0000-0001-6604-3327
                https://orcid.org/0000-0002-9805-9523
                https://orcid.org/0000-0003-4704-3019
                https://orcid.org/0000-0001-8554-3802
                https://orcid.org/0000-0002-7468-2871
                Article
                antioxidants-10-00039
                10.3390/antiox10010039
                7824104
                33396350
                04fe46d9-c099-46ad-8dfc-1dfd8cb5a1c1
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 07 November 2020
                : 27 December 2020
                Categories
                Review

                nrf2,renal disease,acute kidney injury,oxidative stress,and inflammatory response

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