{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T02:34:23Z","timestamp":1774319663362,"version":"3.50.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>An association between genetic variants in the genes <jats:italic>HFE<\/jats:italic>, <jats:italic>HJV<\/jats:italic>, <jats:italic>BMP4<\/jats:italic> and arterial hypertension has been shown earlier. Proteins encoded by these genes participate in the signalling routes leading eventually to the production of the peptide hormone hepcidin. Mutations in these genes have been associated with the abnormal production of hepcidin in the body. This finding led to studies exploring the possible role of hepcidin in regulating the activity of blood pressure related renin-angiotensin system enzymes. We used molecular modelling to find out if it is possible for hepcidin to bind to the active site of the renin-angiotensin system enzymes, especially renin. Fluorometric assays were used to evaluate the inhibitory effect of hepcidin on renin as well as angiotensin converting enzymes 1 and 2. Finally, bio-layer interferometry technique was used to study hepcidin binding to renin. The molecular modelling showed that hepcidin seems to have similar binding properties to the renin active site as angiotensinogen does. Based on fluorometric enzyme activity assay, hepcidin has an inhibitory effect on renin <jats:italic>in vitro<\/jats:italic>, too. However, angiotensin converting enzymes 1 and 2 were not inhibited remarkably by hepcidin-25. In bio-layer interferometry analysis hepcidin-renin binding was concentration dependent. Our results suggest that hepcidin could act as an inhibitor to the renin. Nowadays, there is no known biological inhibitor for renin <jats:italic>in vivo<\/jats:italic> and our finding may thus have important clinical implications.<\/jats:p>","DOI":"10.1371\/journal.pone.0267343","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T17:32:26Z","timestamp":1650475946000},"page":"e0267343","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hepcidin is potential regulator for renin activity"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3657-1169","authenticated-orcid":true,"given":"Jaakko","family":"Piesanen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jarkko","family":"Valjakka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanna","family":"Niemel\u00e4","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjut","family":"Borgenstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seppo","family":"Nikkari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9357-1480","authenticated-orcid":true,"given":"Vesa","family":"Hyt\u00f6nen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juha","family":"M\u00e4\u00e4tt\u00e4","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9647-642X","authenticated-orcid":true,"given":"Tarja","family":"Kunnas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"pone.0267343.ref001","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.bbadis.2015.03.011","article-title":"An overview of molecular basis of iron metabolism regulation and the associated pathologies","volume":"1852","author":"B Silva","year":"2015","journal-title":"Biochimica et biophysica acta. Molecular basis of disease."},{"key":"pone.0267343.ref002","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3945\/an.116.013961","article-title":"Regulation of the Iron Homeostatic Hormone Hepcidin.","volume":"8","author":"V Sangkhae","year":"2017","journal-title":"Advances in nutrition (Bethesda, Md.)."},{"key":"pone.0267343.ref003","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.phrs.2016.11.010","article-title":"Therapeutic potential of hepcidin \u2212 the master regulator of iron metabolism","volume":"115","author":"D Vyoral","year":"2017","journal-title":"Pharmacological research"},{"key":"pone.0267343.ref004","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1172\/JCI31370","article-title":"Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs).","volume":"117","author":"C Peyssonnaux","year":"2007","journal-title":"The Journal of clinical investigation"},{"key":"pone.0267343.ref005","doi-asserted-by":"crossref","first-page":"4635","DOI":"10.1172\/JCI63924","article-title":"Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis","volume":"122","author":"Q Liu","year":"2012","journal-title":"The Journal of clinical investigation"},{"key":"pone.0267343.ref006","doi-asserted-by":"crossref","first-page":"827","DOI":"10.3324\/haematol.2011.056119","article-title":"Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis","volume":"97","author":"M Mastrogiannaki","year":"2012","journal-title":"Haematologica"},{"key":"pone.0267343.ref007","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1182\/blood-2015-12-639112","article-title":"Hepcidin in the diagnosis of iron disorders","volume":"127","author":"D Girelli","year":"2016","journal-title":"Blood"},{"key":"pone.0267343.ref008","doi-asserted-by":"crossref","first-page":"104664","DOI":"10.1016\/j.phrs.2020.104664","article-title":"The role of hepcidin and iron homeostasis in atherosclerosis","volume":"153","author":"F Wunderer","year":"2020","journal-title":"Pharmacological research"},{"key":"pone.0267343.ref009","first-page":"849","article-title":"Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study).","volume":"65","author":"TB Grammer","year":"2019","journal-title":"Clinical chemistry (Baltimore, Md.)."},{"key":"pone.0267343.ref010","doi-asserted-by":"crossref","first-page":"e0134635","DOI":"10.1371\/journal.pone.0134635","article-title":"Iron Stores, Hepcidin, and Aortic Stiffness in Individuals with Hypertension.","volume":"10","author":"L Valenti","year":"2015","journal-title":"PloS one"},{"key":"pone.0267343.ref011","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1161\/ATVBAHA.113.302381","article-title":"Serum hepcidin is associated with presence of plaque in postmenopausal women of a general population","volume":"34","author":"TE Galesloot","year":"2014","journal-title":"Arteriosclerosis, thrombosis, and vascular biology"},{"key":"pone.0267343.ref012","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12863-015-0246-4","article-title":"Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?","volume":"16","author":"TE Galesloot","year":"2015","journal-title":"BMC genetics"},{"key":"pone.0267343.ref013","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.arcmed.2015.07.007","article-title":"Circulating Hepcidin Is Independently Associated with Systolic Blood Pressure in Apparently Healthy Individuals","volume":"46","author":"MF Su\u00e1rez-Orteg\u00f3n","year":"2015","journal-title":"Archives of Medical Research"},{"key":"pone.0267343.ref014","doi-asserted-by":"crossref","first-page":"e464","DOI":"10.1097\/MD.0000000000000464","article-title":"Genetic Variant Coding for Iron Regulatory Protein HFE Contributes to Hypertension, the TAMRISK Study.","volume":"94","author":"KM M\u00e4\u00e4tt\u00e4","year":"2015","journal-title":"Medicine (Baltimore)."},{"key":"pone.0267343.ref015","doi-asserted-by":"crossref","first-page":"e6052","DOI":"10.1097\/MD.0000000000006052","article-title":"Minor variant of rs 16827043 in the iron regulator hemojuvelin gene (HJV) contributes to hypertension: The TAMRISK study.","volume":"96","author":"ST Nikkari","year":"2017","journal-title":"Medicine (Baltimore)."},{"key":"pone.0267343.ref016","doi-asserted-by":"crossref","first-page":"e9362","DOI":"10.1097\/MD.0000000000009362","article-title":"Genetic variation in bone morphogenetic proteins family members (BMPs 2 and 4) and hypertension risk in middle-aged men: The TAMRISK study.","volume":"96","author":"JVI Piesanen","year":"2017","journal-title":"Medicine (Baltimore)."},{"key":"pone.0267343.ref017","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1161\/HYPERTENSIONAHA.118.11730","article-title":"HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study","volume":"73","author":"S Selvaraj","year":"2019","journal-title":"Hypertension (Dallas, Tex. 1979)."},{"key":"pone.0267343.ref018","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1111\/j.1365-2796.2010.02217.x","article-title":"Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy","volume":"268","author":"C Ellervik","year":"2010","journal-title":"Journal of internal medicine"},{"key":"pone.0267343.ref019","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1291\/hypres.30.195","article-title":"Angiotensin II-Induced Regulation of the Expression and Localization of Iron Metabolism-Related Genes in the Rat Kidney","volume":"30","author":"N Ishizaka","year":"2007","journal-title":"Hypertension Research"},{"key":"pone.0267343.ref020","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s00394-014-0749-1","article-title":"Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice","volume":"54","author":"S Tajima","year":"2015","journal-title":"Eur J Nutr"},{"key":"pone.0267343.ref021","doi-asserted-by":"crossref","first-page":"W419","DOI":"10.1093\/nar\/gkv456","article-title":"CABS-dock web server for the flexible docking of peptides to proteins without prior knowledge of the binding site","volume":"43","author":"M Kurcinski","year":"2015","journal-title":"Nucleic acids research"},{"key":"pone.0267343.ref022","first-page":"1771","article-title":"ZDOCK server: interactive docking prediction of protein-protein complexes and symmetric multimers","volume":"30","author":"BG Pierce","year":"2014","journal-title":"Computer applications in the biosciences"},{"key":"pone.0267343.ref023","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/prot.22570","article-title":"Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8","volume":"77","author":"E Krieger","year":"2009","journal-title":"Proteins, structure, function, and bioinformatics."},{"key":"pone.0267343.ref024","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1074\/jbc.RA118.006608","article-title":"Structural basis for the specificity of renin-mediated angiotensinogen cleavage","volume":"294","author":"Y Yan","year":"2019","journal-title":"The Journal of biological chemistry"},{"key":"pone.0267343.ref025","author":"T Giese","year":"2015","journal-title":"Crystal structure of an engineered lipocalin (Anticalin) in complex with human hepcidin."},{"key":"pone.0267343.ref026","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"HM Berman","year":"2000","journal-title":"Nucleic acids research"},{"key":"pone.0267343.ref027","doi-asserted-by":"crossref","first-page":"S162","DOI":"10.1002\/elps.200900140","article-title":"Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: A historical perspective","volume":"30","author":"N Guex","year":"2009","journal-title":"Electrophoresis"},{"key":"pone.0267343.ref028","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera?A visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"Journal of computational chemistry"},{"key":"pone.0267343.ref029","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jprot.2012.08.006","article-title":"Serum levels of the hepcidin-20 isoform in a large general population: The Val Borbera study","volume":"76","author":"N Campostrini","year":"2012","journal-title":"Journal of proteomics"},{"key":"pone.0267343.ref030","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.semnephrol.2018.10.006","article-title":"Iron Homeostasis in Healthy Kidney and its Role in Acute Kidney Injury.","volume":"39","author":"Y Scindia","year":"2019","journal-title":"Seminars in nephrology."},{"key":"pone.0267343.ref031","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1620\/tjem.218.93","article-title":"Serum hepcidin-20 is elevated during the acute phase of myocardial infarction","volume":"218","author":"H Suzuki","year":"2009","journal-title":"Tohoku journal of experimental medicine"},{"key":"pone.0267343.ref032","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1677\/joe.1.05729","article-title":"The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney","volume":"184","author":"H Kulaksiz","year":"2005","journal-title":"Journal of endocrinology"},{"key":"pone.0267343.ref033","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.2337\/dc13-0528","article-title":"Iron status and survival in diabetic patients with coronary artery disease","volume":"36","author":"B Ponikowska","year":"2013","journal-title":"Diabetes care"},{"key":"pone.0267343.ref034","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.ijcard.2014.10.152","article-title":"The incidental relationship between serum ferritin levels and hypertension","volume":"183","author":"J Ryoo","year":"2014","journal-title":"International Journal of Cardiology"},{"key":"pone.0267343.ref035","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ajh.2011.241","article-title":"Increased serum ferritin predicts the development of hypertension among middle-aged men","volume":"25","author":"MK Kim","year":"2012","journal-title":"American Journal of Hypertension"},{"key":"pone.0267343.ref036","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1097\/00004872-200208000-00013","article-title":"Increased serum ferritin is common in men with essential hypertension","volume":"20","author":"A Piperno","year":"2002","journal-title":"Journal of hypertension"},{"key":"pone.0267343.ref037","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/tox.21899","article-title":"Elevated serum ferritin and mercury concentrations are associated with hypertension; analysis of the fourth and fifth Korea national health and nutrition examination survey (KNHANES IV-2, 3, 2008\u20132009 and V-1, 2010).","volume":"30","author":"B Choi","year":"2015","journal-title":"Environmental toxicology."},{"key":"pone.0267343.ref038","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1741-7015-10-54","article-title":"Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial.","volume":"10","author":"KS Houschyar","year":"2012","journal-title":"BMC medicine."},{"key":"pone.0267343.ref039","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.ahj.2013.01.017","article-title":"Iron deficiency in chronic heart failure: An international pooled analysis","volume":"165","author":"IT Klip","year":"2013","journal-title":"The American heart journal"},{"key":"pone.0267343.ref040","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1002\/ejhf.473","article-title":"Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials.","volume":"18","author":"EA Jankowska","year":"2016","journal-title":"European journal of heart failure"},{"key":"pone.0267343.ref041","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1182\/blood-2002-10-3235","article-title":"Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein","volume":"101","author":"E Nemeth","year":"2003","journal-title":"Blood"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0267343","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T17:32:55Z","timestamp":1650475975000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0267343"}},"subtitle":[],"editor":[{"given":"Wolfgang E.B.","family":"Jelkmann","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,4,20]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0267343","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,20]]}}}