{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:42:07Z","timestamp":1792158127761,"version":"4.4.0"},"reference-count":39,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T00:00:00Z","timestamp":1671235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium\u2013glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1\u03b2, IL-8, and TGF-\u03b21. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with \u03b1-smooth muscle actin (\u03b1-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms232416107","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T05:25:46Z","timestamp":1671427546000},"page":"16107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9302-1633","authenticated-orcid":false,"given":"Theodoros","family":"Eleftheriadis","sequence":"first","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Pissas","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Filippidis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Efthymiadi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7564-2724","authenticated-orcid":false,"given":"Vassilios","family":"Liakopoulos","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Stefanidis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Faculty of Medicine, University of Thessaly, Biopolis, Mezourlo Hill, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in Patients with Chronic Kidney Disease","volume":"383","author":"Heerspink","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1681\/ASN.2021020167","article-title":"Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease","volume":"32","author":"Chertow","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1161\/CIRCULATIONAHA.118.037418","article-title":"Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging","volume":"140","author":"Kidokoro","year":"2019","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1002\/dmrr.2407","article-title":"Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis","volume":"29","author":"Maeda","year":"2013","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1055\/s-0035-1555791","article-title":"Tofogliflozin, A Highly Selective Inhibitor of SGLT2 Blocks Proinflammatory and Proapoptotic Effects of Glucose Overload on Proximal Tubular Cells Partly by Suppressing Oxidative Stress Generation","volume":"48","author":"Ishibashi","year":"2015","journal-title":"Horm. Metab. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e00239","DOI":"10.1002\/prp2.239","article-title":"Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice","volume":"4","author":"Hatanaka","year":"2016","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s11255-020-02481-3","article-title":"A unifying model of glucotoxicity in human renal proximal tubular epithelial cells and the effect of the SGLT2 inhibitor dapagliflozin","volume":"52","author":"Eleftheriadis","year":"2020","journal-title":"Int. Urol. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrneph.2016.170","article-title":"Renal, metabolic and cardiovascular considerations of SGLT2 inhibition","volume":"13","author":"DeFronzo","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nrneph.2012.19","article-title":"Glomerular hyperfiltration: Definitions, mechanisms and clinical implications","volume":"8","author":"Helal","year":"2012","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1056\/NEJMoa1614329","article-title":"Single-Nephron Glomerular Filtration Rate in Healthy Adults","volume":"376","author":"Denic","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"F1563","DOI":"10.1152\/ajprenal.90302.2008","article-title":"Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy","volume":"295","author":"Verzola","year":"2008","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11892-020-01314-y","article-title":"Role of Senescent Renal Cells in Pathophysiology of Diabetic Kidney Disease","volume":"20","author":"Wiley","year":"2020","journal-title":"Curr. Diabetes Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1681\/ASN.2018121251","article-title":"Cellular Senescence in the Kidney","volume":"30","author":"Docherty","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1093\/ndt\/gfu230","article-title":"Cell cycle arrest and the evolution of chronic kidney disease from acute kidney injury","volume":"30","author":"Canaud","year":"2014","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e001380","DOI":"10.1161\/JAHA.114.001380","article-title":"Validated Contemporary Risk Model of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions: Insights From the National Cardiovascular Data Registry Cath-PCI Registry","volume":"3","author":"Tsai","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.jdiacomp.2014.05.010","article-title":"Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy","volume":"28","author":"Kitada","year":"2014","journal-title":"J. Diabetes Its Complicat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s40262-013-0104-3","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-transporter Type 2","volume":"53","author":"Kasichayanula","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1124\/jpet.116.232025","article-title":"Interaction of the Sodium\/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2","volume":"358","author":"Ohgaki","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1681\/ASN.2016050510","article-title":"Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule","volume":"28","author":"Ghezzi","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/bcp.12056","article-title":"The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus","volume":"76","author":"Kasichayanula","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.12659\/MSM.902530","article-title":"Therapeutic Effect of Sodium Glucose Co-Transporter 2 Inhibitor Dapagliflozin on Renal Cell Carcinoma","volume":"23","author":"Kuang","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.2147\/DMSO.S243170","article-title":"Empagliflozin Protects Against Proximal Renal Tubular Cell Injury Induced by High Glucose via Regulation of Hypoxia-Inducible Factor 1-Alpha","volume":"13","author":"Ndibalema","year":"2020","journal-title":"Diabetes Metab. Syndr. Obes. Targets Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Singh, A., Kukreti, R., Saso, L., and Kukreti, S. (2022). Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes. Molecules, 27.","DOI":"10.3390\/molecules27030950"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s40620-020-00749-6","article-title":"Targeting oxidative stress and anti-oxidant defence in diabetic kidney disease","volume":"33","author":"Cooper","year":"2020","journal-title":"J. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s11255-017-1733-5","article-title":"Allopurinol protects human glomerular endothelial cells from high glucose-induced reactive oxygen species generation, p53 overexpression and endothelial dysfunction","volume":"50","author":"Eleftheriadis","year":"2017","journal-title":"Int. Urol. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6135","DOI":"10.1038\/sj.onc.1203124","article-title":"ATM: A mediator of multiple responses to genotoxic stress","volume":"18","author":"Rotman","year":"1999","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2016.04.008","article-title":"Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage","volume":"42","author":"Karimian","year":"2016","journal-title":"DNA Repair."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1242\/jcs.064501","article-title":"p53 at a glance","volume":"123","author":"Brady","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of Cellular Senescence","volume":"28","author":"Nehme","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1002\/ijc.27316","article-title":"Cellular senescence and tumor suppressor gene p16","volume":"130","author":"Rayess","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1016\/j.celrep.2018.03.002","article-title":"Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage- and Histone Methylation-Dependent Pathways","volume":"22","author":"Ito","year":"2018","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1083\/jcb.123.3.513","article-title":"The cell proliferation-associated antigen of antibody Ki-67: A very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins","volume":"123","author":"Duchrow","year":"1993","journal-title":"J. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.tem.2015.08.001","article-title":"The IL-1 Pathway in Type 2 Diabetes and Cardiovascular Complications","volume":"26","author":"Herder","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cytogfr.2016.09.002","article-title":"Endothelial-to-mesenchymal transition: Cytokine-mediated pathways that determine endothelial fibrosis under inflammatory conditions","volume":"33","author":"Riedel","year":"2017","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"592","DOI":"10.3109\/0886022X.2013.773836","article-title":"The Renal Endothelium in Diabetic Nephropathy","volume":"35","author":"Eleftheriadis","year":"2013","journal-title":"Ren. Fail."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"631","DOI":"10.3390\/cells4040631","article-title":"Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy: Fact or Fiction?","volume":"4","author":"Loeffler","year":"2015","journal-title":"Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1111\/jcmm.17356","article-title":"Research progress of endothelial-mesenchymal transition in diabetic kidney disease","volume":"26","author":"Chen","year":"2022","journal-title":"J. Cell. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"155828","DOI":"10.1016\/j.cyto.2022.155828","article-title":"Interleukin-8: An evolving chemokine","volume":"153","author":"Matsushima","year":"2022","journal-title":"Cytokine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1159\/000320749","article-title":"Rapid Progression of Diabetic Nephropathy Is Linked to Inflammation and Episodes of Acute Renal Failure","volume":"32","author":"Kelly","year":"2010","journal-title":"Am. J. Nephrol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16107\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:43:19Z","timestamp":1760146999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,17]]},"references-count":39,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232416107"],"URL":"https:\/\/doi.org\/10.3390\/ijms232416107","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,17]]}}}