{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T05:13:39Z","timestamp":1739510019667,"version":"3.37.0"},"reference-count":46,"publisher":"Portland Press Ltd.","issue":"03","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation, DFG","award":["SFB1365"],"award-info":[{"award-number":["SFB1365"]}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,2,12]]},"abstract":"<jats:p>Angiotensin II (Ang II) is the most active peptide hormone produced by the renin\u2013angiotensin system (RAS). Genetic deletion of genes that ultimately restrict Ang II formation has been shown to result in marked anemia in mice. In this study, adult mice with a genetic deletion of the RAS precursor protein angiotensinogen (Agt-KO) were used. Experimental analyses included capillary hematocrit, hemogram, plasma and tissue iron quantifications, expression analyses of genes encoding relevant proteins for body iron homeostasis in different organs, as well as plasma and urine hepcidin quantifications. As previously reported, Agt-KO were anemic with reduced red blood cell counts. Interestingly, we found that they presented microcytic anemia based on the reduced red blood cell volume. In agreement, plasma quantification of iron revealed lower levels of circulating iron in Agt-KO. The major body iron stores, namely in the liver and spleen, were also depleted in the RAS-deficient line. Hepatic hepcidin expression was reduced, as well as one of its major regulators, BMP6, as a result of the iron deficiency. However, plasma hepcidin levels were unexpectedly increased in Agt-KO. We confirm the typical morphological alterations and impaired renal function of Agt-KO and conclude that hepcidin accumulates in the circulation due to the reduced glomerular filtration in Agt-KO, and therefore identified the culprit of iron deficiency in Agt-KO. Collectively, the data demonstrated that the severe anemia developed in RAS-deficient mice is exacerbated by iron deficiency which is secondary to the renal damage-induced hepcidin accumulation in the circulation.<\/jats:p>","DOI":"10.1042\/cs20241789","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T17:49:35Z","timestamp":1738000175000},"page":"247-258","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Renal damage-induced hepcidin accumulation contributes to anemia in angiotensinogen-deficient mice"],"prefix":"10.1042","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-6896","authenticated-orcid":false,"given":"Andr\u00e9 F.","family":"Rodrigues","sequence":"first","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"2German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6897-3499","authenticated-orcid":false,"given":"Laura","family":"Boreggio","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"3Charit\u00e9 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2667-9253","authenticated-orcid":false,"given":"Tetiana","family":"Lahuta","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"4Bogomoletz Institute of Physiology, Department of General and Molecular Pathophysiology, NAS of Ukraine, Kyiv, Ukraine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8500-489X","authenticated-orcid":false,"given":"Fatimunnisa","family":"Qadri","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6071-5433","authenticated-orcid":false,"given":"Natalia","family":"Alenina","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"2German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-734X","authenticated-orcid":false,"given":"Carlos C.","family":"Barros","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"5Nutrition Faculty, Federal University of Pelotas - UFPel, Pelotas, RS, Brazil"},{"name":"6Technological Development Center, Federal University of Pelotas - UFPel, Pelotas, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9373-4753","authenticated-orcid":false,"given":"Mihail","family":"Todiras","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"7Nicolae Testemi\u021banu State University of Medicine and Pharmacy, Chisinau, Moldova"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4780-4164","authenticated-orcid":false,"given":"Michael","family":"Bader","sequence":"additional","affiliation":[{"name":"1Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany"},{"name":"2German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany"},{"name":"8Experimental and Clinical Research Center, a cooperation between the Max-Delbr\u00fcck-Center for Molecular Medicine in the Helmholtz Association and the Charit\u00e9 - Universit\u00e4tsmedizin Berlin, Berlin, Germany"},{"name":"9Institute for Biology, University of L\u00fcbeck, L\u00fcbeck, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"2025021308220579400_CS-2024-1789C1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1146\/annurev.pharmtox.010909.105610","article-title":"Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy","volume":"50","author":"Bader","year":"2010","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2025021308220579400_CS-2024-1789C2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41577-021-00634-8","article-title":"Crosstalk between the renin-angiotensin, complement and kallikrein-kinin systems in inflammation","volume":"22","author":"Bekassy","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"2025021308220579400_CS-2024-1789C3","doi-asserted-by":"crossref","DOI":"10.1016\/j.bcp.2023.115805","article-title":"The contribution of the AT1 receptor to erythropoiesis","volume":"217","author":"Rodrigues","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"2025021308220579400_CS-2024-1789C4","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1172\/JCI10557","article-title":"Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice","volume":"106","author":"Cole","year":"2000","journal-title":"J. Clin. Invest."},{"key":"2025021308220579400_CS-2024-1789C5","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0129484","article-title":"Erythropoiesis and blood pressure are regulated via AT1 receptor by distinctive pathways","volume":"10","author":"Kato","year":"2015","journal-title":"Plos one"},{"key":"2025021308220579400_CS-2024-1789C6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1634\/stemcells.18-4-287","article-title":"Effect of angiotensin II on hematopoietic progenitor cell proliferation","volume":"18","author":"Rodgers","year":"2000","journal-title":"Stem Cells"},{"key":"2025021308220579400_CS-2024-1789C7","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1172\/JCI119769","article-title":"Angiotensin II stimulates proliferation of normal early erythroid progenitors","volume":"100","author":"Mrug","year":"1997","journal-title":"J. Clin. Invest."},{"key":"2025021308220579400_CS-2024-1789C8","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1124\/mol.113.091157","article-title":"Mechanism of erythropoietin regulation by angiotensin II","volume":"85","author":"Kim","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"2025021308220579400_CS-2024-1789C9","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.3390\/molecules26175399","article-title":"Effects of angiotensin II on erythropoietin production in the kidney and liver","volume":"26","author":"Yasuoka","year":"2021","journal-title":"Molecules"},{"key":"2025021308220579400_CS-2024-1789C10","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1096\/fj.05-3820fje","article-title":"Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type 1a receptor","volume":"19","author":"Kato","year":"2005","journal-title":"FASEB J."},{"key":"2025021308220579400_CS-2024-1789C11","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1042\/CS20210072","article-title":"Increased angiotensin II formation in the brain modulates cardiovascular homeostasis and erythropoiesis","volume":"135","author":"Rodrigues","year":"2021","journal-title":"Clin. Sci."},{"key":"2025021308220579400_CS-2024-1789C12","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1161\/HYPERTENSIONAHA.117.09283","article-title":"Chronic stimulation of renin cells leads to vascular pathology","volume":"70","author":"Oka","year":"2017","journal-title":"Hypertension"},{"key":"2025021308220579400_CS-2024-1789C13","doi-asserted-by":"crossref","first-page":"31334","DOI":"10.1016\/S0021-9258(18)31697-1","article-title":"Angiotensinogen-deficient mice with hypotension","volume":"269","author":"Tanimoto","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2025021308220579400_CS-2024-1789C14","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1111\/bph.16051","article-title":"Angiotensin deficient FVB\/N mice are normotensive","volume":"180","author":"Rodrigues","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"2025021308220579400_CS-2024-1789C15","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/S0140-6736(82)92430-8","article-title":"Enalapril (mk-421) and the white cell count and haematocrit","volume":"319","author":"Griffing","year":"1982","journal-title":"Lancet"},{"key":"2025021308220579400_CS-2024-1789C16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2131\/jts.6.SupplementII_215","article-title":"Twelve month studies on the chronic toxicity of captopril in rats","volume":"6","author":"Hashimoto","year":"1981","journal-title":"J. Toxicol. Sci."},{"key":"2025021308220579400_CS-2024-1789C17","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1007\/s00467-021-05018-7","article-title":"Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor","volume":"36","author":"Viering","year":"2021","journal-title":"Pediatr. Nephrol."},{"key":"2025021308220579400_CS-2024-1789C18","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1007\/s00467-020-04524-4","article-title":"Bi-allelic mutations in renin-angiotensin system genes, associated with renal tubular dysgenesis, can also present as a progressive chronic kidney disease","volume":"35","author":"Fila","year":"2020","journal-title":"Pediatr. Nephrol."},{"key":"2025021308220579400_CS-2024-1789C19","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/ng2059","article-title":"Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice","volume":"39","author":"Wang","year":"2007","journal-title":"Nat. Genet."},{"key":"2025021308220579400_CS-2024-1789C20","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.14441","article-title":"Distinct iron homeostasis in C57BL\/6 and Balb\/c mouse strains","volume":"8","author":"Saha","year":"2020","journal-title":"Physiol. Rep."},{"key":"2025021308220579400_CS-2024-1789C21","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1073\/pnas.051630898","article-title":"Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis","volume":"98","author":"Fleming","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2025021308220579400_CS-2024-1789C22","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.bbrc.2019.09.141","article-title":"Genetic background influences hepcidin response to iron imbalance in a mouse model of hemolytic anemia (Congenital erythropoietic porphyria)","volume":"520","author":"Lefebvre","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025021308220579400_CS-2024-1789C23","doi-asserted-by":"crossref","DOI":"10.1080\/10641963.2023.2180019","article-title":"Angiotensin II-induced vascular endothelial cells ferroptosis via P53-ALOX12 signal axis","volume":"45","author":"Liu","year":"2023","journal-title":"Clin. Exp. Hypertens."},{"key":"2025021308220579400_CS-2024-1789C24","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/hr.2010.63","article-title":"Effect of angiotensin II on iron-transporting protein expression and subsequent intracellular labile iron concentration in human glomerular endothelial cells","volume":"33","author":"Tajima","year":"2010","journal-title":"Hypertens. Res."},{"key":"2025021308220579400_CS-2024-1789C25","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1007\/s11064-014-1285-3","article-title":"Angiotensin II inhibits iron uptake and release in cultured neurons","volume":"39","author":"Liu","year":"2014","journal-title":"Neurochem. Res."},{"key":"2025021308220579400_CS-2024-1789C26","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1139\/y2012-104","article-title":"Angiotensin II promotes iron accumulation and depresses PGI\u2082 and NO synthesis in endothelial cells: effects of losartan and propranolol analogs","volume":"90","author":"Mak","year":"2012","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"2025021308220579400_CS-2024-1789C27","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":"Ishizaka","year":"2007","journal-title":"Hypertens. Res."},{"key":"2025021308220579400_CS-2024-1789C28","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":"Tajima","year":"2015","journal-title":"Eur. J. Nutr."},{"key":"2025021308220579400_CS-2024-1789C29","doi-asserted-by":"crossref","first-page":"4038","DOI":"10.1182\/blood-2006-10-051755","article-title":"Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation","volume":"109","author":"Roy","year":"2007","journal-title":"Blood"},{"key":"2025021308220579400_CS-2024-1789C30","doi-asserted-by":"crossref","first-page":"4596","DOI":"10.1073\/pnas.072632499","article-title":"Severe iron deficiency anemia in transgenic mice expressing liver hepcidin","volume":"99","author":"Nicolas","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2025021308220579400_CS-2024-1789C31","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3324\/haematol.2019.232124","article-title":"Iron metabolism and iron disorders revisited in the hepcidin era","volume":"105","author":"Camaschella","year":"2020","journal-title":"Haematologica"},{"key":"2025021308220579400_CS-2024-1789C32","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1159\/000243791","article-title":"The role of hepcidin in iron metabolism","volume":"122","author":"Nemeth","year":"2009","journal-title":"Acta Haematol."},{"key":"2025021308220579400_CS-2024-1789C33","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1182\/blood-2008-04-149773","article-title":"Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis","volume":"112","author":"Folgueras","year":"2008","journal-title":"Blood"},{"key":"2025021308220579400_CS-2024-1789C34","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/ajh.26311","article-title":"Iron distribution in different tissues of homozygous mask (msk\/msk) mice and the effects of oral iron treatments","volume":"96","author":"Asperti","year":"2021","journal-title":"Am. J. Hematol."},{"key":"2025021308220579400_CS-2024-1789C35","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.2215\/CJN.08161109","article-title":"Reduction of serum hepcidin by hemodialysis in pediatric and adult patients","volume":"5","author":"Zaritsky","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"2025021308220579400_CS-2024-1789C36","doi-asserted-by":"crossref","first-page":"231","DOI":"10.5414\/CN108906","article-title":"Hepcidin clearance is associated with erythropoietin requirement in stable hemodialysis patients","volume":"87","author":"Ashby","year":"2017","journal-title":"Clin. Nephrol."},{"key":"2025021308220579400_CS-2024-1789C37","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1046\/j.1523-1755.1998.00788.x","article-title":"Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption","volume":"53","author":"Okubo","year":"1998","journal-title":"Kidney Int."},{"key":"2025021308220579400_CS-2024-1789C38","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1681\/ASN.2004060490","article-title":"Ren1c homozygous null mice are hypotensive and polyuric, but heterozygotes are indistinguishable from wild-type","volume":"16","author":"Takahashi","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025021308220579400_CS-2024-1789C39","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0087484","article-title":"Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of ACE-\/- mice","volume":"9","author":"Chattopadhyay","year":"2014","journal-title":"Plos one"},{"key":"2025021308220579400_CS-2024-1789C40","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.154337","article-title":"Inhibition of the renin-angiotensin system causes concentric hypertrophy of renal arterioles in mice and humans","volume":"6","author":"Watanabe","year":"2021","journal-title":"JCI Insight"},{"key":"2025021308220579400_CS-2024-1789C41","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1186\/s12882-023-03426-5","article-title":"Effect of iron administration on the aortic iron content and vascular calcification in phosphorus-loaded chronic kidney disease rats","volume":"24","author":"Nakanishi","year":"2023","journal-title":"BMC Nephrol."},{"key":"2025021308220579400_CS-2024-1789C42","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.kint.2021.10.036","article-title":"Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin","volume":"101","author":"Hanudel","year":"2022","journal-title":"Kidney Int."},{"key":"2025021308220579400_CS-2024-1789C43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00467-011-1832-y","article-title":"Hepcidin in anemia of chronic kidney disease: review for the pediatric nephrologist","volume":"27","author":"Atkinson","year":"2012","journal-title":"Pediatr. Nephrol."},{"key":"2025021308220579400_CS-2024-1789C44","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.ekir.2018.12.006","article-title":"Interleukin-6 contributes to the development of anemia in juvenile CKD","volume":"4","author":"Akchurin","year":"2019","journal-title":"Kidney Int. Rep."},{"key":"2025021308220579400_CS-2024-1789C45","doi-asserted-by":"crossref","first-page":"F877","DOI":"10.1152\/ajprenal.00089.2016","article-title":"Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease","volume":"311","author":"Akchurin","year":"2016","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2025021308220579400_CS-2024-1789C46","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1182\/blood-2008-03-143354","article-title":"Iron regulates phosphorylation of Smad1\/5\/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver","volume":"112","author":"Kautz","year":"2008","journal-title":"Blood"}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/139\/03\/247\/966980\/cs-2024-1789.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/139\/03\/247\/966980\/cs-2024-1789.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T08:22:49Z","timestamp":1739434969000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/139\/03\/247\/235599\/Renal-damage-induced-hepcidin-accumulation"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":46,"journal-issue":{"issue":"03","published-print":{"date-parts":[[2025,2,12]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20241789","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"type":"print","value":"0143-5221"},{"type":"electronic","value":"1470-8736"}],"subject":[],"published-other":{"date-parts":[[2025,2]]},"published":{"date-parts":[[2025,2]]}}}