{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:38:53Z","timestamp":1791833933806,"version":"4.3.4"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003825","name":"Magyar Tudom\u00e1nyos Akad\u00e9mia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011019","name":"Nemzeti Kutat\u00e1si Fejleszt\u00e9si \u00e9s Innov\u00e1ci\u00f3s Hivatal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011019","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Aims:<\/jats:bold> Chronic kidney disease (CKD) is frequently associated with other chronic diseases including anemia. Daprodustat (DPD) is a prolyl hydroxylase inhibitor, a member of a family of those new generation drugs that increase erythropoiesis <jats:italic>via<\/jats:italic> activation of the hypoxia-inducible factor 1 (HIF-1) pathway. Previous studies showed that HIF-1 activation is ultimately linked to acceleration of vascular calcification. We aimed to investigate the effect of DPD on high phosphate-induced calcification.<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> We investigated the effect of DPD on calcification in primary human aortic vascular smooth muscle cells (VSMCs), in mouse aorta rings, and an adenine and high phosphate-induced CKD murine model. DPD stabilized HIF-1\u03b1 and HIF-2\u03b1 and activated the HIF-1 pathway in VSMCs. Treatment with DPD increased phosphate-induced calcification in cultured VSMCs and murine aorta rings. Oral administration of DPD to adenine and high phosphate-induced CKD mice corrected anemia but increased aortic calcification as assessed by osteosense staining. The inhibition of the transcriptional activity of HIF-1 by chetomin or silencing of HIF-1\u03b1 attenuated the effect of DPD on VSMC calcification.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Clinical studies with a long follow-up period are needed to evaluate the possible risk of sustained activation of HIF-1 by DPD in accelerating medial calcification in CKD patients with hyperphosphatemia.<\/jats:p>","DOI":"10.3389\/fphar.2022.798053","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T05:50:48Z","timestamp":1644213048000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["Daprodustat Accelerates High Phosphate-Induced Calcification Through the Activation of HIF-1 Signaling"],"prefix":"10.3389","volume":"13","author":[{"given":"Andrea","family":"T\u00f3th","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1vid M\u00e1t\u00e9","family":"Csiki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"B\u00e9la","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enik\u0151","family":"Balogh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e9ta","family":"Lente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haneen","family":"Ababneh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1rp\u00e1d","family":"Sz\u00f6\u0151r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikt\u00f3ria","family":"Jeney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.2215\/CJN.16011219","article-title":"Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial","volume":"15","author":"Akizawa","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1124\/JPET.117.242503","article-title":"Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia","volume":"363","author":"Ariazi","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1681\/ASN.2011111078","article-title":"Mechanisms of Anemia in CKD","volume":"23","author":"Babitt","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1161\/ATVBAHA.119.312509","article-title":"Hypoxia Triggers Osteochondrogenic Differentiation of Vascular Smooth Muscle Cells in an HIF-1 (Hypoxia-Inducible Factor 1)-Dependent and Reactive Oxygen Species-dependent Manner","volume":"39","author":"Balogh","year":"2019","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1681\/ASN.2019020213","article-title":"Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment","volume":"31","author":"Batchelor","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1007\/s40265-020-01384-y","article-title":"Daprodustat: First Approval","volume":"80","author":"Dhillon","year":"2020","journal-title":"Drugs"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e270","DOI":"10.1371\/journal.pmed.0040270","article-title":"Renal Function and Risk of Coronary Heart Disease in General Populations: New Prospective Study and Systematic Review","volume":"4","author":"Di Angelantonio","year":"2007","journal-title":"Plos Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1056\/NEJM198701083160203","article-title":"Correction of the Anemia of End-Stage Renal Disease with Recombinant Human Erythropoietin. Results of a Combined Phase I and II Clinical Trial","volume":"316","author":"Eschbach","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1159\/000496492","article-title":"Iron Deficiency Anemia in Chronic Kidney Disease","volume":"142","author":"Gafter-Gvili","year":"2019","journal-title":"Acta Haematol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/ki.2008.644","article-title":"The Emerging Role of Phosphate in Vascular Calcification","volume":"75","author":"Giachelli","year":"2009","journal-title":"Kidney Int."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1378\/chest.130.4.1025","article-title":"Abnormalities of the Bronchial Arteries in Asthma","volume":"130","author":"Green","year":"2006","journal-title":"Chest"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1681\/ASN.2008070804","article-title":"HIF in Kidney Disease and Development","volume":"20","author":"Gunaratnam","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s12325-020-01524-6","article-title":"Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin","volume":"38","author":"Hanna","year":"2021","journal-title":"Adv. Ther."},{"key":"B14","doi-asserted-by":"publisher","first-page":"155","DOI":"10.2147\/TCRM.S293879","article-title":"Profile of Daprodustat in the Treatment of Renal Anemia Due to Chronic Kidney Disease","author":"Ishii","year":"2021","journal-title":"Tcrm"},{"key":"B15","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1126\/science.1059796","article-title":"Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation","volume":"292","author":"Jaakkola","year":"2001","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.87.7.e10","article-title":"Phosphate Regulation of Vascular Smooth Muscle Cell Calcification","volume":"87","author":"Jono","year":"2000","journal-title":"Circ. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1161\/ATVBAHA.119.313224","article-title":"Soluble Uric Acid Promotes Atherosclerosis via AMPK (AMP-Activated Protein Kinase)-Mediated Inflammation","volume":"40","author":"Kimura","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1053\/j.ajkd.2012.07.014","article-title":"Dose of Erythropoiesis-Stimulating Agents and Adverse Outcomes in CKD: A Metaregression Analysis","volume":"61","author":"Koulouridis","year":"2013","journal-title":"Am. J. Kidney Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/S10157-016-1288-2","article-title":"Time to Target Uric Acid to Retard CKD Progression","volume":"21","author":"Kumagai","year":"2017","journal-title":"Clin. Exp. Nephrol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"259","DOI":"10.3389\/fmed.2017.00259","article-title":"Hypoxia Induced Factor in Chronic Kidney Disease: Friend or Foe","volume":"4","author":"Li","year":"2018","journal-title":"Front. Med. (Lausanne)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/S10059-010-0067-2","article-title":"HIF-1 and HIF-2 Transcription Factors-Ssimilar but Not Identical","volume":"29","author":"Loboda","year":"2010","journal-title":"Mol. Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1093\/ndt\/gft033","article-title":"Kidney Disease: Improving Global Outcomes Guidelines on Anaemia Management in Chronic Kidney Disease: A European Renal Best Practice Position Statement","volume":"28","author":"Locatelli","year":"2013","journal-title":"Nephrol. Dial. Transpl."},{"key":"B23","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1159\/000455166","article-title":"Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients","volume":"45","author":"Locatelli","year":"2017","journal-title":"Am. J. Nephrol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1038\/s41588-019-0514-8","article-title":"HDAC9 Is Implicated in Atherosclerotic Aortic Calcification and Affects Vascular Smooth Muscle Cell Phenotype","volume":"51","author":"Malhotra","year":"2019","journal-title":"Nat. Genet."},{"key":"B25","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/S40520-015-0395-3","article-title":"Elevated Serum Uric Acid Is Associated with Vascular Inflammation but Not Coronary Artery Calcification in the Healthy Octogenarians: the Brazilian Study on Healthy Aging","volume":"28","author":"Malik","year":"2016","journal-title":"Aging Clin. Exp. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1681\/ASN.2006070771","article-title":"Metabolic Bone Disease in Chronic Kidney Disease","volume":"18","author":"Martin","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/nrneph.2015.193","article-title":"HIF Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anaemia and beyond","volume":"12","author":"Maxwell","year":"2016","journal-title":"Nat. Rev. Nephrol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1159\/000351175","article-title":"Cardiovascular Toxicity of Epoetin-Alfa in Patients with Chronic Kidney Disease","volume":"37","author":"McCullough","year":"2013","journal-title":"Am. J. Nephrol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1515\/BC.2004.016","article-title":"HIF Hydroxylation and Cellular Oxygen Sensing","volume":"385","author":"Metzen","year":"2004","journal-title":"Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.kint.2016.05.020","article-title":"Hypoxia-inducible Factor-1 Plays a Role in Phosphate-Induced Vascular Smooth Muscle Cell Calcification","volume":"90","author":"Mokas","year":"2016","journal-title":"Kidney Int."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.3389\/FPHYS.2019.01584","article-title":"Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate","volume":"10","author":"Nagy","year":"2020","journal-title":"Front. Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1007\/s00109-007-0278-y","article-title":"Hypoxia and the HIF System in Kidney Disease","volume":"85","author":"Nangaku","year":"2007","journal-title":"J. Mol. Med. (Berl)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3899\/JRHEUM.100639","article-title":"Serum Urate Is Not Associated with Coronary Artery Calcification: the NHLBI Family Heart Study","volume":"38","author":"Neogi","year":"2011","journal-title":"J. Rheumatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"23","DOI":"10.7326\/0003-4819-153-1-201007060-00252","article-title":"Meta-analysis: Erythropoiesis-Stimulating Agents in Patients with Chronic Kidney Disease","volume":"153","author":"Palmer","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"F891","DOI":"10.1152\/ajprenal.00163.2014","article-title":"A Current Understanding of Vascular Calcification in CKD","volume":"307","author":"Paloian","year":"2014","journal-title":"Am. J. Physiol. Ren. Physiol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s40261-016-0378-y","article-title":"The Safety of Erythropoiesis-Stimulating Agents for the Treatment of Anemia Resulting from Chronic Kidney Disease","volume":"36","author":"Robles","year":"2016","journal-title":"Clin. Drug Investig."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2154","DOI":"10.1161\/01.CIR.0000095676.90936.80","article-title":"Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention","volume":"108","author":"Sarnak","year":"2003","journal-title":"Circulation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/sj.ki.5002696","article-title":"Exploring the Biology of Vascular Calcification in Chronic Kidney Disease: What's Circulating","volume":"73","author":"Schoppet","year":"2008","journal-title":"Kidney Int."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0092-8674(01)00518-9","article-title":"HIF-1, O(2), and the 3 PHDs: How Animal Cells Signal Hypoxia to the Nucleus","volume":"107","author":"Semenza","year":"2001","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"5447","DOI":"10.1128\/mcb.12.12.5447","article-title":"A Nuclear Factor Induced by Hypoxia via De Novo Protein Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation","volume":"12","author":"Semenza","year":"1992","journal-title":"Mol. Cel. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.atherosclerosis.2015.04.801","article-title":"Obstructive Sleep Apnea and Abdominal Aortic Calcification: Is There An\u00a0association Independent of Comorbid Risk Factors","volume":"241","author":"Tachikawa","year":"2015","journal-title":"Atherosclerosis"},{"key":"B42","doi-asserted-by":"publisher","first-page":"2233","DOI":"10.1038\/s41598-017-02351-6","article-title":"Development of a Novel Chronic Kidney Disease Mouse Model to Evaluate the Progression of Hyperphosphatemia and Associated mineral Bone Disease","volume":"7","author":"Tani","year":"2017","journal-title":"Sci. Rep."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1016\/S0140-6736(16)32064-5","article-title":"Chronic Kidney Disease","volume":"389","author":"Webster","year":"2017","journal-title":"Lancet"},{"key":"B44","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1136\/thoraxjnl-2012-203151","article-title":"Coronary Artery Calcification Is Increased in Patients with COPD and Associated with Increased Morbidity and Mortality","volume":"69","author":"Williams","year":"2014","journal-title":"Thorax"},{"key":"B45","doi-asserted-by":"publisher","first-page":"19660","DOI":"10.1002\/JCB.29272","article-title":"The Effects of Hyperuricemia on the Differentiation and Proliferation of Osteoblasts and Vascular Smooth Muscle Cells Are Implicated in the Elevated Risk of Osteopenia and Vascular Calcification in Gout: An In Vivo and In Vitro Analysis","volume":"120","author":"Yan","year":"2019","journal-title":"J. Cel. Biochem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.798053\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T11:47:58Z","timestamp":1644493678000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.798053\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,7]]},"references-count":45,"alternative-id":["10.3389\/fphar.2022.798053"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.798053","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,7]]},"article-number":"798053"}}