{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:56:09Z","timestamp":1787957769662,"version":"build-2784847793"},"reference-count":28,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T00:00:00Z","timestamp":1759622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>In chronic kidney disease (CKD), oxidative stress and inflammation contribute to disease progression and CKD-related morbidity. The nuclear factor erythroid 2-related factor 2 (Nrf2) system plays a central role in the cellular response to oxidative and inflammatory stress. In this brief report, we describe our investigation into whether alterations in the gene expression of key Nrf2 pathway components contribute to the endogenous activation of the Nrf2 system previously reported in less advanced CKD. To this end, we quantified the gene expression of Nrf2, its regulatory protein Kelch-like ECH-associated protein 1 (KEAP1), and the Nrf2 downstream target NAD(P)H:quinone oxidoreductase 1 (NQO1) in monocytes from patients in different stages of CKD. We observed significantly elevated NQO1 gene expression in CKD stage G3b compared to CKD stages G1-3a (p &lt; 0.05), G4 (p &lt; 0.01), and G5 (p &lt; 0.001). In contrast, the gene expression levels of Nrf2 and KEAP1 did not differ significantly between CKD stages. These findings suggest that endogenous activation of the Nrf2 system in moderate CKD predominantly reflects functional activation, likely at the protein level, rather than changes in the gene expression of Nrf2 or KEAP1.<\/jats:p>","DOI":"10.3390\/ijms26199693","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"9693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gene Expression of Nrf2 and KEAP1 in Monocytes of Patients with Chronic Kidney Disease (CKD)"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8145-6898","authenticated-orcid":false,"given":"Ahmed","family":"Timimi","sequence":"first","affiliation":[{"name":"Institute of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8855-2448","authenticated-orcid":false,"given":"Subagini","family":"Nagarajah","sequence":"additional","affiliation":[{"name":"Institute of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark"},{"name":"Department of Nephrology, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Tepel","sequence":"additional","affiliation":[{"name":"Institute of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark"},{"name":"Department of Nephrology, Odense University Hospital, 5000 Odense, Denmark"},{"name":"Institute of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3100-8692","authenticated-orcid":false,"given":"Alexandra","family":"Scholze","sequence":"additional","affiliation":[{"name":"Institute of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark"},{"name":"Department of Cardiac, Thoracic, and Vascular Surgery, Odense University Hospital, 5000 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.kisu.2021.11.003","article-title":"Epidemiology of chronic kidney disease: An update 2022","volume":"12","author":"Kovesdy","year":"2022","journal-title":"Kidney Int. Suppl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.2174\/1573403X14666180711124825","article-title":"Chronic Kidney Disease and Cardiovascular Disease: Is there Any Relationship?","volume":"15","author":"Vallianou","year":"2019","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1046\/j.1523-1755.2000.00236.x","article-title":"Increased intracellular reactive oxygen species in patients with end-stage renal failure: Effect of hemodialysis","volume":"58","author":"Tepel","year":"2000","journal-title":"Kidney Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s00059-024-05235-4","article-title":"Increased cardiovascular risk in patients with chronic kidney disease","volume":"49","author":"Vondenhoff","year":"2024","journal-title":"Herz"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"533","DOI":"10.23876\/j.krcp.22.069","article-title":"Pathomechanism of oxidative stress in cardiovascularrenal remodeling and therapeutic strategies","volume":"41","author":"Ravarotto","year":"2022","journal-title":"Kidney Res. Clin. Pr."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ngo, V., and Duennwald, M.L. (2022). Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease. Antioxidants, 11.","DOI":"10.3390\/antiox11122345"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Aranda-Rivera, A.K., Cruz-Gregorio, A., Pedraza-Chaverri, J., and Scholze, A. (2022). Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls. Antioxidants, 11.","DOI":"10.3390\/antiox11020246"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tibs.2014.02.002","article-title":"The Nrf2 regulatory network provides an interface between redox and intermediary metabolism","volume":"39","author":"Hayes","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9091879","DOI":"10.1155\/2017\/9091879","article-title":"Expression of the NRF2 Target Gene NQO1 Is Enhanced in Mononuclear Cells in Human Chronic Kidney Disease","volume":"2017","author":"Shen","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1093\/ndt\/gfab031","article-title":"Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: Alterations, interventions and relation to morbidity","volume":"37","author":"Shen","year":"2022","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.trsl.2024.11.001","article-title":"Early vascular aging in chronic kidney disease: Focus on microvascular maintenance, senescence signature and potential therapeutics","volume":"275","author":"Arefin","year":"2025","journal-title":"Transl. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1007\/s11255-015-1135-5","article-title":"NRF2 and NF-\u03baB mRNA expression in chronic kidney disease: A focus on nondialysis patients","volume":"47","author":"Leal","year":"2015","journal-title":"Int. Urol. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"F1122","DOI":"10.1152\/ajprenal.00202.2019","article-title":"Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease","volume":"317","author":"Liu","year":"2019","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rasmussen, M., Hansen, K.H., and Scholze, A. (2023). Nrf2 Protein Serum Concentration in Human CKD Shows a Biphasic Behavior. Antioxidants, 12.","DOI":"10.3390\/antiox12040932"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1016\/j.bbadis.2019.05.010","article-title":"Activated NF-\u03baB\/Nrf2 and Wnt\/\u03b2-catenin pathways are associated with lipid metabolism in CKD patients with microalbuminuria and macroalbuminuria","volume":"1865","author":"Feng","year":"2019","journal-title":"Biochim. et Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e14566","DOI":"10.14814\/phy2.14566","article-title":"The NRF2 stimulating agent, tin protoporphyrin, activates protective cytokine pathways in healthy human subjects and in patients with chronic kidney disease","volume":"8","author":"Zager","year":"2020","journal-title":"Physiol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1379\/CSC-270.1","article-title":"Oxidative stress and cellular stress response in diabetic nephropathy","volume":"12","author":"Calabrese","year":"2007","journal-title":"Cell Stress Chaperon-"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1515\/hsz-2016-0135","article-title":"Genetic association of NAD(P)H quinone oxidoreductase (NQO1*2) polymorphism with NQO1 levels and risk of diabetic nephropathy","volume":"397","author":"Sharma","year":"2016","journal-title":"Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bian, Y., Dong, J., Zhou, Z., Zhou, H., Xu, Y., Zhang, Q., Chen, C., and Pi, J. (2025). The spatiotemporal and paradoxical roles of NRF2 in renal toxicity and kidney diseases. Redox Biol., 79.","DOI":"10.1016\/j.redox.2024.103476"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rispoli, R.M., Popolo, A., De Fabrizio, V., Bianca, R.D.d.V., Autore, G., Dalli, J., and Marzocco, S. (2025). Targeting Inflammatory Imbalance in Chronic Kidney Disease: Focus on Anti-Inflammatory and Resolution Mediators. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073072"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1093\/gerona\/glz131","article-title":"The Association of a Single-Nucleotide Polymorphism in the Nuclear Factor (Erythroid-Derived 2)-Like 2 Gene With Adverse Drug Reactions, Multimorbidity, and Frailty in Older People","volume":"75","author":"Scutt","year":"2019","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"737","DOI":"10.2147\/IJGM.S351263","article-title":"The Age-Specific Features and Clinical Significance of NRF2 and MAPK10 Expression in HCC Patients","volume":"15","author":"Atyah","year":"2022","journal-title":"Int. J. Gen. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.freeradbiomed.2024.05.034","article-title":"Sulforaphane upregulates the mRNA expression of NRF2 and NQO1 in non-dialysis patients with chronic kidney disease","volume":"221","author":"Ribeiro","year":"2024","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1053\/j.jrn.2023.08.008","article-title":"Sulforaphane Supplementation Did Not Modulate NRF2 and NF-kB mRNA Expressions in Hemodialysis Patients","volume":"34","author":"Ribeiro","year":"2024","journal-title":"J. Ren. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bolati, D., Shimizu, H., Yisireyili, M., Nishijima, F., and Niwa, T. (2013). Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-\u03baB. BMC Nephrol., 14.","DOI":"10.1186\/1471-2369-14-56"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1159\/000493874","article-title":"N-Acetylcysteine Suppresses LPS-Induced Pathological Angiogenesis","volume":"49","author":"Zhang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_27","first-page":"1","article-title":"Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease","volume":"3","author":"Levin","year":"2013","journal-title":"Kidney Int. Suppl."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A New Equation to Estimate Glomerular Filtration Rate","volume":"150","author":"Levey","year":"2009","journal-title":"Ann. Intern. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9693\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:08:02Z","timestamp":1759763282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,5]]},"references-count":28,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199693"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199693","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,5]]}}}