{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T21:02:32Z","timestamp":1783976552744,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012283","name":"Chiayi Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPG6J0071"],"award-info":[{"award-number":["CMRPG6J0071"]}],"id":[{"id":"10.13039\/501100012283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012283","name":"Chiayi Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPG6J0072"],"award-info":[{"award-number":["CMRPG6J0072"]}],"id":[{"id":"10.13039\/501100012283","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hypertension is an important public health challenge, affecting up to 30\u201350% of adults worldwide. Several epidemiological studies indicate that high blood pressure originates in fetal life\u2014the so-called programming effect or developmental origin of hypertension. Iron-deficiency anemia has become one of the most prevalent nutritional problems globally. Previous animal experiments have shown that prenatal iron-deficiency anemia adversely affects offspring hypertension. However, the underlying mechanism remains unclear. We used a maternal low-iron diet Sprague Dawley rat model to study changes in blood pressure, the renal renin-angiotensin system, oxidative stress, inflammation, and sodium transporters in adult male offspring. Our study revealed that 16-week-old male offspring born to mothers with low dietary iron throughout pregnancy and the lactation period had (1) higher blood pressure, (2) increased renal cortex angiotensin II receptor type 1 and angiotensin-converting enzyme abundance, (3) decreased renal cortex angiotensin II receptor type 2 and MAS abundance, and (4) increased renal 8-hydroxy-2\u2032-deoxyguanosine and interleukin-6 abundance. Improving the iron status of pregnant mothers could influence the development of hypertension in their offspring.<\/jats:p>","DOI":"10.3390\/ijms23158294","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T21:11:05Z","timestamp":1658956265000},"page":"8294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Maternal Iron Deficiency Programs Rat Offspring Hypertension in Relation to Renin\u2014Angiotensin System and Oxidative Stress"],"prefix":"10.3390","volume":"23","author":[{"given":"Ya-Hui","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi 61344, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Hsuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi 61344, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Hao","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi 61344, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1242-8760","authenticated-orcid":false,"given":"Hong-Ren","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-6407","authenticated-orcid":false,"given":"You-Lin","family":"Tain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7403-288X","authenticated-orcid":false,"given":"Li-Tung","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiunn-Ming","family":"Sheen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Chiayi Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Chiayi 61344, Taiwan"},{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0140-6736(05)17741-1","article-title":"Global burden of hypertension: Analysis of worldwide data","volume":"365","author":"Kearney","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1161\/01.STR.27.11.2020","article-title":"Risk factors for cerebral hemorrhage in the era of well-controlled hypertension. Melbourne Risk Factor Study (MERFS) Group","volume":"27","author":"Thrift","year":"1996","journal-title":"Stroke"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7S","DOI":"10.1093\/ajh\/7.7.7S","article-title":"Established risk factors and coronary artery disease: The Framingham Study","volume":"7","author":"Wilson","year":"1994","journal-title":"Am. J. Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1001\/archinte.161.9.1207","article-title":"Prevalence of high blood pressure and elevated serum creatinine level in the United States: Findings from the third National Health and Nutrition Examination Survey (1988\u20131994)","volume":"161","author":"Coresh","year":"2001","journal-title":"Arch. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1001\/archinte.165.8.923","article-title":"Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease","volume":"165","author":"Hsu","year":"2005","journal-title":"Arch. Intern. Med."},{"key":"ref_6","first-page":"547809","article-title":"Essential hypertension: An approach to its etiology and neurogenic pathophysiology","volume":"2013","year":"2013","journal-title":"Int. J. Hypertens."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1161\/HYPERTENSIONAHA.111.181784","article-title":"Systematic review and meta-analysis of preterm birth and later systolic blood pressure","volume":"59","author":"Monuteaux","year":"2012","journal-title":"Hypertension"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.acvd.2011.10.006","article-title":"Birth weight and subsequent blood pressure: A meta-analysis","volume":"105","author":"Mu","year":"2012","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/hr.2013.33","article-title":"The associations of high birth weight with blood pressure and hypertension in later life: A systematic review and meta-analysis","volume":"36","author":"Zhang","year":"2013","journal-title":"Hypertens. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/978-981-10-5526-3_5","article-title":"Fetal Origins of Hypertension","volume":"1012","author":"Arima","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/apha.12702","article-title":"Pregnancy as a critical window for blood pressure regulation in mother and child: Programming and reprogramming","volume":"219","author":"Paauw","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0140-6736(07)61235-5","article-title":"Nutritional iron deficiency","volume":"370","author":"Zimmerman","year":"2007","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0140-6736(89)90710-1","article-title":"Weight in infancy and death from ischaemic heart disease","volume":"2","author":"Barker","year":"1989","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra0708473","article-title":"Effect of in utero and early-life conditions on adult health and disease","volume":"359","author":"Gluckman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1056\/NEJMe058187","article-title":"Developmental origins of health and disease","volume":"353","author":"Gillman","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1152\/physrev.00015.2015","article-title":"In utero origins of hypertension: Mechanisms and targets for therapy","volume":"96","author":"Morton","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1042\/CS20150611","article-title":"Gender differences in the developmental programming of cardiovascular disease","volume":"130","author":"Dasinger","year":"2016","journal-title":"Clin. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/bdrc.21021","article-title":"Long-term effects of prenatal stress and glucocorticoid exposure","volume":"96","author":"Painter","year":"2012","journal-title":"Birth. Defects Res. C Embryo. Today"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1161\/HYPERTENSIONAHA.107.092890","article-title":"Developmental programming of hypertension: Insight from animal models of nutritional manipulation","volume":"52","author":"Ojeda","year":"2008","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1093\/jn\/137.4.1066","article-title":"Maternal nutrition, low nephron number, and hypertension in later life: Pathways of nutritional programming","volume":"137","author":"Bagby","year":"2007","journal-title":"J. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"760580","DOI":"10.1155\/2012\/760580","article-title":"Developmental programming of hypertension and kidney disease","volume":"2012","author":"Chong","year":"2012","journal-title":"Int. J. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hsu, C.N., and Tain, Y.L. (2018). The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension. Nutrients, 10.","DOI":"10.3390\/nu10121917"},{"key":"ref_23","first-page":"1","article-title":"Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention","volume":"47","author":"Yip","year":"1998","journal-title":"MMWR Recomm. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Brannon, P.M., and Taylor, C.L. (2017). Iron Supplementation during Pregnancy and Infancy: Uncertainties and Implications for Research and Policy. Nutrients, 9.","DOI":"10.3390\/nu9121327"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/j.1365-2141.2011.09012.x","article-title":"UK guidelines on the management of iron deficiency in pregnancy","volume":"156","author":"Pavord","year":"2012","journal-title":"Br. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hsieh, H.Y., Chen, Y.C., Hsu, M.H., Yu, H.R., Su, C.H., Tain, Y.L., Huang, L.T., and Sheen, J.M. (2020). Maternal Iron Deficiency Programs Offspring Cognition and Its Relationship with Gastrointestinal Microbiota and Metabolites. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17176070"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1053\/meta.2001.22516","article-title":"Effects of maternal iron restriction in the rat on blood pressure, glucose tolerance, and serum lipids in the 3-month-old offspring","volume":"50","author":"Lewis","year":"2001","journal-title":"Metabolism"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1079\/BJN2002656","article-title":"Long-term programming of blood pressure by maternal dietary iron restriction in the rat","volume":"88","author":"Lewis","year":"2002","journal-title":"Br. J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1113\/jphysiol.2003.051383","article-title":"Iron deficiency during pregnancy affects postnatal blood pressure in the rat","volume":"552","author":"Gambling","year":"2003","journal-title":"J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1055\/s-0035-1556742","article-title":"Maternal Iron Status in Pregnancy and Long-Term Health Outcomes in the Offspring","volume":"4","author":"Alwan","year":"2015","journal-title":"J. Pediatr. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3945\/ajcn.116.150482","article-title":"Lower systolic blood pressure at age 7 y in low-birth-weight children who received iron supplements in infancy: Results from a randomized controlled trial","volume":"106","author":"Lindberg","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0300-9629(94)00177-U","article-title":"Captopril normalises systolic blood pressure in rats with hypertension induced by fetal exposure to maternal low protein diets","volume":"110","author":"Jackson","year":"1995","journal-title":"Comp. Biochem. Physiol. A Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1046\/j.1523-1755.2001.00484.x","article-title":"Prenatal programming of adult hypertension in the rat","volume":"59","author":"Vehaskari","year":"2001","journal-title":"Kidney Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"F262","DOI":"10.1152\/ajprenal.00055.2004","article-title":"Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension","volume":"287","author":"Vehaskari","year":"2004","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1089\/ars.2013.5259","article-title":"Oxidative stress in hypertension: Role of the kidney","volume":"20","author":"Araujo","year":"2014","journal-title":"Antioxid. Redox. Signal"},{"key":"ref_36","first-page":"907.3","article-title":"Early changes on proximal tubule Na+-ATPase activity precede blood pressure elevation and renal dysfunction induced by intrauterine undernutrition: Reprogramming by alpha-tocopherol","volume":"27","author":"Farias","year":"2013","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hsu, C.N., Lin, Y.J., Yu, H.R., Lin, I.C., Sheen, J.M., Huang, L.T., and Tain, Y.L. (2019). Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163957"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1111\/j.1440-1681.2009.05212.x","article-title":"Placental oxidative stress in malnourished rats and changes in kidney proximal tubule sodium ATPases in offspring","volume":"36","author":"Lara","year":"2009","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46573","DOI":"10.1038\/srep46573","article-title":"Modest and severe maternal iron deficiency in pregnancy are associated with fetal anaemia and organ-specific hypoxia in rats","volume":"7","author":"Woodman","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1096\/fj.201701080R","article-title":"Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver","volume":"32","author":"Woodman","year":"2018","journal-title":"FASEB J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4103\/1110-1067.186392","article-title":"Effects of oral iron (ferrous versus ferric) supplementation on oxidative stress and antioxidant status in pregnant women with iron deficiency: Controlled trial","volume":"41","author":"Aly","year":"2016","journal-title":"Egypt J. Haematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJM199901143400207","article-title":"Atherosclerosis--an inflammatory disease","volume":"340","author":"Ross","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jsgi.2005.10.003","article-title":"Maternal interleukin-6: Marker of fetal growth and adiposity","volume":"13","author":"Radaelli","year":"2006","journal-title":"J. Soc. Gynecol. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2014.03.025","article-title":"Maternal obesity and high-fat diet program offspring metabolic syndrome","volume":"211","author":"Desai","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/j.1745-7254.2007.00593.x","article-title":"Prenatal exposure to lipopolysaccharide results in increases in blood pressure and body weight in rats","volume":"28","author":"Wei","year":"2007","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1210\/endo.142.7.8238","article-title":"The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta -hydroxysteroid dehydrogenase: Potential molecular mechanisms underlying the programming of hypertension in utero","volume":"142","author":"Bertram","year":"2001","journal-title":"Endocrinology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"F202","DOI":"10.1152\/ajprenal.00358.2001","article-title":"Upregulation of renal BSC1 and TSC in prenatally programmed hypertension","volume":"283","author":"Manning","year":"2002","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3389\/fphys.2015.00377","article-title":"Maternal Melatonin Therapy Rescues Prenatal Dexamethasone and Postnatal High-Fat Diet Induced Programmed Hypertension in Male Rat Offspring","volume":"6","author":"Tain","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_49","first-page":"2333794X211041337","article-title":"The Effect of Iron Deficiency Anemia and Different Treatment Methods on DNA Damage: 8-hydroxy-2-deoxyguanosine Level","volume":"8","author":"Akarsu","year":"2021","journal-title":"Glob. Pediatr. Health"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s11906-013-0413-9","article-title":"Innate immunity in hypertension","volume":"16","author":"Mian","year":"2014","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1161\/HYPERTENSIONAHA.110.163576","article-title":"Inflammation, immunity, and hypertension","volume":"57","author":"Harrison","year":"2011","journal-title":"Hypertension"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1097\/01.hjh.0000166840.63312.12","article-title":"Enhanced levels of platelet P-selectin and circulating cytokines in young patients with mild arterial hypertension","volume":"23","author":"Stumpf","year":"2005","journal-title":"J. Hypertens."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"F704","DOI":"10.1152\/ajprenal.00030.2009","article-title":"Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1","volume":"297","author":"Vallon","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5607","DOI":"10.1038\/s41598-018-24010-0","article-title":"Combined maternal and postnatal high-fat diet leads to metabolic syndrome and is effectively reversed by resveratrol: A multiple-organ study","volume":"8","author":"Sheen","year":"2018","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8294\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:57:31Z","timestamp":1760140651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,27]]},"references-count":54,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158294"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158294","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,27]]}}}