{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:56:57Z","timestamp":1789923417282,"version":"4.0.1"},"reference-count":49,"publisher":"CSIRO Publishing","issue":"7","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":4313,"URL":"https:\/\/doi.org\/10.1071\/journalslicense"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,22]]},"abstract":"<jats:p>A developmental insult that restricts growth in the first generation has the potential to program disease in subsequent generations. The aim of this study was to ascertain transgenerational growth and cardio\u2013renal effects, via the maternal line, in a rat model of utero\u2013placental insufficiency. Bilateral uterine vessel ligation or sham surgery (offspring termed first generation; F1 Restricted and Control, respectively) was performed in WKY rats. F1 Restricted and Control females were mated with normal males to produce second generation (F2) offspring (Restricted and Control) studied from fetal (embryonic Day 20) to adult (12 months) life. F2 Restricted male and female fetuses had reduced (P &amp;lt; 0.05) nephron number (down 15\u201322%) but this deficit was not sustained postnatally and levels were similar to Controls at Day 35. F2 Restricted males, but not females, developed elevated (+16 mmHg, P &amp;lt; 0.05) systolic blood pressure at 6 months of age, which was sustained to 9 months. This was not explained by alterations to intra-renal or plasma components of the renin\u2013angiotensin system. In a rat model of utero\u2013placental insufficiency, we report alterations to F2 kidney development and sex-specific adult hypertension. This study demonstrates that low birthweight can have far-reaching effects that extend into the next generation.<\/jats:p>","DOI":"10.1071\/rd13133","type":"journal-article","created":{"date-parts":[[2013,8,4]],"date-time":"2013-08-04T20:56:56Z","timestamp":1375649816000},"page":"1032-1043","source":"Crossref","is-referenced-by-count":38,"title":["Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats"],"prefix":"10.1071","volume":"26","author":[{"given":"Linda A.","family":"Gallo","sequence":"first","affiliation":[{"name":"ADepartment of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia."},{"name":"EPresent address: Mater Research, Translational Research Institute, Woolloongabba, Qld 4102, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Tran","sequence":"additional","affiliation":[{"name":"ADepartment of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luise A.","family":"Cullen-McEwen","sequence":"additional","affiliation":[{"name":"BDepartment of Anatomy and Developmental Biology, Monash University, Clayton, Vic. 3168, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate M.","family":"Denton","sequence":"additional","affiliation":[{"name":"CDepartment of Physiology, Monash University, Clayton, Vic. 3168, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Jefferies","sequence":"additional","affiliation":[{"name":"ADepartment of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen M.","family":"Moritz","sequence":"additional","affiliation":[{"name":"DSchool of Biomedical Sciences, The University of Queensland, St Lucia, Qld 4067, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Wlodek","sequence":"additional","affiliation":[{"name":"ADepartment of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia."},{"name":"FCorresponding author. Email: m.wlodek@unimelb.edu.au"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"67","published-online":{"date-parts":[[2013,8,5]]},"reference":[{"key":"2025102819443619600_R1","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1095\/BIOLREPROD.105.045807","article-title":"Placental insufficiency leads to developmental hypertension and mesenteric artery dysfunction in two generations of Sprague\u2013Dawley rat offspring.","volume":"74","author":"Anderson","year":"2006","journal-title":"Biol. Reprod."},{"key":"2025102819443619600_R2","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1113\/JPHYSIOL.2004.072009","article-title":"Developmental programming of the metabolic syndrome by maternal nutritional imbalance: how strong is the evidence from experimental models in mammals?","volume":"561","author":"Armitage","year":"2004","journal-title":"J. Physiol."},{"key":"2025102819443619600_R3","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1136\/BMJ.311.6998.171","article-title":"Fetal origins of coronary heart disease.","volume":"311","author":"Barker","year":"1995","journal-title":"BMJ"},{"key":"2025102819443619600_R4","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0140-6736(89)90710-1","article-title":"Weight in infancy and death from ischaemic heart disease.","volume":"334","author":"Barker","year":"1989","journal-title":"Lancet"},{"key":"2025102819443619600_R5","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1161\/HYPERTENSIONAHA.108.114256","article-title":"Immediate postnatal growth is associated with blood pressure in young adulthood: the Barry Caerphilly Growth Study.","volume":"52","author":"Ben-Shlomo","year":"2008","journal-title":"Hypertension"},{"key":"2025102819443619600_R6","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/S0074-7696(08)62497-3","article-title":"Analysing renal glomeruli with the new stereology.","volume":"161","author":"Bertram","year":"1995","journal-title":"Int. Rev. Cytol."},{"key":"2025102819443619600_R7","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1203\/01.PDR.0000065731.00639.02","article-title":"Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring.","volume":"54","author":"Brawley","year":"2003","journal-title":"Pediatr. Res."},{"key":"2025102819443619600_R8","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1093\/AJH\/1.4.335","article-title":"Glomeruli and blood pressure. Less of one, more the other?","volume":"1","author":"Brenner","year":"1988","journal-title":"Am. J. Hypertens."},{"key":"2025102819443619600_R9","doi-asserted-by":"crossref","first-page":"F1448","DOI":"10.1152\/ajprenal.00055.2011","article-title":"A design-based method for estimating glomerular number in the developing kidney.","volume":"300","author":"Cullen-McEwen","year":"2011","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2025102819443619600_R10","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/978-1-61779-851-1_10","article-title":"Estimating nephron number in the developing kidney using the physical dissector\/fractionator combination.","volume":"886","author":"Cullen-McEwen","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"2025102819443619600_R11","doi-asserted-by":"crossref","first-page":"R697","DOI":"10.1152\/ajpregu.00766.2006","article-title":"Physiological and molecular mechanisms governing sexual dimorphism of kidney, cardiac and vascular function.","volume":"292","author":"Denton","year":"2007","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2025102819443619600_R12","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1161\/01.HYP.36.5.790","article-title":"Fetal and childhood growth and hypertension in adult life.","volume":"36","author":"Eriksson","year":"2000","journal-title":"Hypertension"},{"key":"2025102819443619600_R13","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1136\/BMJ.322.7292.949","article-title":"Early growth and coronary heart disease in later life: longitudinal study.","volume":"322","author":"Eriksson","year":"2001","journal-title":"BMJ"},{"key":"2025102819443619600_R14","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1161\/HYPERTENSIONAHA.112.195578","article-title":"Long-term alteration in maternal blood pressure and renal function after pregnancy in normal and growth-restricted rats.","volume":"60","author":"Gallo","year":"2012","journal-title":"Hypertension"},{"key":"2025102819443619600_R15","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/S00441-012-1411-Y","article-title":"Maternal adaptations and inheritance in the transgenerational programming of adult disease.","volume":"349","author":"Gallo","year":"2012","journal-title":"Cell Tissue Res."},{"key":"2025102819443619600_R16","doi-asserted-by":"publisher","first-page":"4337","DOI":"10.1096\/FJ.12-210401","article-title":"Pregnancy in aged rats that were born small: cardio\u2013renal and metabolic adaptations and second-generation fetal growth.","volume":"26","author":"Gallo","year":"2012","journal-title":"FASEB J."},{"key":"2025102819443619600_R17","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1113\/jphysiol.2011.219147","article-title":"Cardio\u2013renal and metabolic adaptations during pregnancy in female rats born small: implications for maternal health and second-generation fetal growth.","volume":"590","author":"Gallo","year":"2012","journal-title":"J. Physiol."},{"key":"2025102819443619600_R18","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1203\/PDR.0B013E3182042A20","article-title":"Sex differences in the ovine fetal cortisol response to stress.","volume":"69","author":"Giussani","year":"2011","journal-title":"Pediatr. Res."},{"key":"2025102819443619600_R19","doi-asserted-by":"crossref","first-page":"R804","DOI":"10.1152\/ajpregu.00725.2006","article-title":"Placental insufficiency results in temporal alterations in the renin\u2013angiotensin system in male hypertensive growth restricted offspring.","volume":"293","author":"Grigore","year":"2007","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2025102819443619600_R20","doi-asserted-by":"publisher","first-page":"S121","DOI":"10.1016\/J.GENM.2008.03.012","article-title":"Sex differences in the fetal programming of hypertension.","volume":"5","author":"Grigore","year":"2008","journal-title":"Gend. Med."},{"key":"2025102819443619600_R21","doi-asserted-by":"crossref","first-page":"F1668","DOI":"10.1152\/ajprenal.00163.2009","article-title":"Is nephrogenesis affected by preterm birth? Studies in a non-human primate model.","volume":"297","author":"Gubhaju","year":"2009","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2025102819443619600_R22","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1136\/HRT.2004.047381","article-title":"Endothelial dysfunction and cardiovascular disease: the role of predictive adaptive responses.","volume":"91","author":"Hanson","year":"2005","journal-title":"Heart"},{"key":"2025102819443619600_R23","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1017\/S0007114508057607","article-title":"Intergenerational programming of impaired nephrogenesis and hypertension in rats following maternal protein restriction during pregnancy.","volume":"101","author":"Harrison","year":"2009","journal-title":"Br. J. Nutr."},{"key":"2025102819443619600_R24","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1034\/J.1600-0412.2002.810204.X","article-title":"The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations.","volume":"81","author":"Henriksen","year":"2002","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"2025102819443619600_R25","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1046\/J.1523-1755.1999.00633.X","article-title":"A new dimension to the Barker hypothesis: low birthweight and susceptibility to renal disease.","volume":"56","author":"Hoy","year":"1999","journal-title":"Kidney Int."},{"key":"2025102819443619600_R26","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1681\/ASN.2005020172","article-title":"Nephron number, hypertension, renal disease and renal failure.","volume":"16","author":"Hoy","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025102819443619600_R27","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1203\/PDR.0B013E31822A65A3","article-title":"IUGR in the absence of postnatal \u201ccatch-up\u201d growth leads to improved whole body insulin sensitivity in rat offspring.","volume":"70","author":"Lim","year":"2011","journal-title":"Pediatr. Res."},{"key":"2025102819443619600_R28","doi-asserted-by":"publisher","first-page":"3375","DOI":"10.1113\/JPHYSIOL.2012.230011","article-title":"Utero\u2013placental insufficiency programmes vascular dysfunction in non-pregnant rats: compensatory adaptations in pregnancy.","volume":"590","author":"Mazzuca","year":"2012","journal-title":"J. Physiol."},{"key":"2025102819443619600_R29","doi-asserted-by":"publisher","first-page":"207","DOI":"10.2459\/JCM.0B013E32833178ED","article-title":"Gender determinants of cardiovascular risk factors and diseases.","volume":"11","author":"Mercuro","year":"2010","journal-title":"J. Cardiovasc. Med."},{"key":"2025102819443619600_R30","doi-asserted-by":"publisher","first-page":"2635","DOI":"10.1113\/JPHYSIOL.2009.170407","article-title":"Utero\u2013placental insufficiency causes a nephron deficit, modest renal insufficiency but no hypertension with ageing in female rats.","volume":"587","author":"Moritz","year":"2009","journal-title":"J. Physiol."},{"key":"2025102819443619600_R31","doi-asserted-by":"crossref","first-page":"R539","DOI":"10.1152\/ajpregu.00628.2007","article-title":"Effects of utero\u2013placental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.","volume":"294","author":"O\u2019Dowd","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2025102819443619600_R32","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1161\/HYPERTENSIONAHA.107.091785","article-title":"Oestrogen protects against increased blood pressure in postpubertal female growth-restricted offspring.","volume":"50","author":"Ojeda","year":"2007","journal-title":"Hypertension"},{"key":"2025102819443619600_R33","doi-asserted-by":"crossref","first-page":"R758","DOI":"10.1152\/ajpregu.00311.2006","article-title":"Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth-restricted offspring.","volume":"292","author":"Ojeda","year":"2007","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2025102819443619600_R34","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1111\/J.1471-0528.2008.01822.X","article-title":"Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life.","volume":"115","author":"Painter","year":"2008","journal-title":"BJOG"},{"key":"2025102819443619600_R35","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/J.LFS.2012.01.017","article-title":"Implications of maternal nutrient restriction in transgenerational programming of hypertension and endothelial dysfunction across F1\u2013F3 offspring.","volume":"90","author":"Ponzio","year":"2012","journal-title":"Life Sci."},{"issue":"Suppl 2","key":"2025102819443619600_R36","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.1016\/J.PLACENTA.2012.07.018","article-title":"The next generation of disease risk: are the effects of prenatal nutrition transmitted across generations? Evidence from animal and human studies.","volume":"33","author":"Roseboom","year":"2012","journal-title":"Placenta"},{"key":"2025102819443619600_R37","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/BF03165784","article-title":"Influence of intrauterine growth restriction on renal function in the adult rat.","volume":"63","author":"Schreuder","year":"2007","journal-title":"J. Physiol. Biochem."},{"key":"2025102819443619600_R38","doi-asserted-by":"publisher","first-page":"2279","DOI":"10.2337\/DIABETES.50.10.2279","article-title":"Intrauterine growth retardation leads to the development of Type 2 diabetes in the rat.","volume":"50","author":"Simmons","year":"2001","journal-title":"Diabetes"},{"key":"2025102819443619600_R39","doi-asserted-by":"crossref","first-page":"F319","DOI":"10.1152\/ajprenal.00139.2011","article-title":"Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade.","volume":"301","author":"Singh","year":"2011","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2025102819443619600_R40","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1113\/JPHYSIOL.2002.026120","article-title":"Maternal protein restriction in the rat impairs resistance artery but not conduit artery function in pregnant offspring.","volume":"547","author":"Torrens","year":"2003","journal-title":"J. Physiol."},{"key":"2025102819443619600_R41","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1017\/S0007114508921747","article-title":"Transmission of raised blood pressure and endothelial dysfunction to the F2 generation induced by maternal protein restriction in the F0, in the absence of dietary challenge in the F1 generation.","volume":"100","author":"Torrens","year":"2008","journal-title":"Br. J. Nutr."},{"key":"2025102819443619600_R42","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1097\/MOP.0B013E328336EBC9","article-title":"Prenatal programming of kidney disease.","volume":"22","author":"Vehaskari","year":"2010","journal-title":"Curr. Opin. Pediatr."},{"key":"2025102819443619600_R43","doi-asserted-by":"publisher","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":"2025102819443619600_R44","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. Renal Physiol."},{"key":"2025102819443619600_R45","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1681\/ASN.2007020252","article-title":"Low birthweight increases risk for end-stage renal disease.","volume":"19","author":"Vikse","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025102819443619600_R46","doi-asserted-by":"crossref","first-page":"E861","DOI":"10.1152\/ajpendo.00037.2008","article-title":"Utero\u2013placental insufficiency and reducing litter size alters skeletal muscle mitochondrial biogenesis in a sex-specific manner in the adult rat.","volume":"294","author":"Wadley","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2025102819443619600_R47","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1681\/ASN.2007010015","article-title":"Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.","volume":"18","author":"Wlodek","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"2025102819443619600_R48","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/KI.2008.153","article-title":"Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats.","volume":"74","author":"Wlodek","year":"2008","journal-title":"Kidney Int."},{"key":"2025102819443619600_R49","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1007\/S00125-006-0175-X","article-title":"A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products.","volume":"49","author":"Zimanyi","year":"2006","journal-title":"Diabetologia"}],"container-title":["Reproduction, Fertility and Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/connectsci.au\/rd\/article-pdf\/26\/7\/1032\/311364\/rd13133.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/connectsci.au\/rd\/article-pdf\/26\/7\/1032\/311364\/rd13133.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:44:47Z","timestamp":1761695087000},"score":1,"resource":{"primary":{"URL":"https:\/\/connectsci.au\/rd\/article\/26\/7\/1032\/50068\/Transgenerational-programming-of-fetal-nephron"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,8,5]]},"references-count":49,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2014,8,22]]}},"URL":"https:\/\/doi.org\/10.1071\/rd13133","relation":{},"ISSN":["1031-3613","1448-5990"],"issn-type":[{"value":"1031-3613","type":"print"},{"value":"1448-5990","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,8,5]]}}}