Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Dietary-induced gestational iron deficiency inhibits postnatal tissue iron delivery and postpones the cessation of active nephrogenesis in rats

Mary Y. Sun A B , Joseph C. Woolley A , Sharon E. Blohowiak A , Zachary R. Smith A , Ashajyothi M. Siddappa C D , Ronald R. Magness A B and Pamela J. Kling A E

A Departments of Pediatrics, University of Wisconsin, Neonatology, Meriter UnityPoint Hospital, 202 S. Park St., Madison, WI 53715, USA.

B Obstetrics and Gynecology Perinatal Research Laboratories, University of Wisconsin, Meriter UnityPoint Hospital, 202 S. Park St., Madison, WI 53715, USA.

C Department of Pediatrics, Division of Neonatology, Hennepin County Medical Center and University of Minnesota, , Minneapolis, MN, USA.

D Center for Neurobehavioral Development, 516 Delaware St. SE, Minneapolis, MN 55455, USA.

E Corresponding author. Email: pkling@pediatrics.wisc.edu

Reproduction, Fertility and Development 29(5) 855-866 https://doi.org/10.1071/RD15358
Submitted: 2 September 2015  Accepted: 14 December 2015   Published: 15 February 2016

Abstract

Gestational iron deficiency (ID) can alter developmental programming through impaired nephron endowment, leading to adult hypertension, but nephrogenesis is unstudied. Iron status and renal development during dietary-induced gestational ID (<6 mg Fe kg–1 diet from Gestational Day 2 to Postnatal Day (PND) 7) were compared with control rats (198 mg Fe kg–1 diet). On PND2–PND10, PND15, PND30 and PND45, blood and tissue iron status were assessed. Nephrogenic zone maturation (PND2–PND10), radial glomerular counts (RGCs), glomerular size density and total planar surface area (PND15 and PND30) were also assessed. Blood pressure (BP) was measured in offspring. ID rats were smaller, exhibiting lower erythrocyte and tissue iron than control rats (PND2–PND10), but these parameters returned to control values by PND30–PND45. Relative kidney iron (µg g–1 wet weight) at PND2-PND10 was directly related to transport iron measures. In ID rats, the maturation of the active nephrogenic zone was later than control. RGCs, glomerular size, glomerular density, and glomerular planar surface area were lower than control at PND15, but returned to control by PND30. After weaning, the kidney weight/rat weight ratio (mg g–1) was heavier in ID than control rats. BP readings at PND45 were lower in ID than control rats. Altered kidney maturation and renal adaptations may contribute to glomerular size, early hyperfiltration and long-term renal function.

Additional keywords: anemia, development, developmental programming, glomeruli, hypertension, kidneys, nutrition.


References

Beard, J. L., Wiesinger, J. A., and Connor, J. R. (2003). Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev. Neurosci. 25, 308–315.
Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats.CrossRef | 1:CAS:528:DC%2BD3sXovVOgtrg%3D&md5=d0c30da71bdb5891d56b9f1dc3a95418CAS | 14614257PubMed | open url image1

Blohowiak, S. E., Chen, M. E., Repyak, K. S., Baumann-Blackmore, N. L., Carlton, D. P., Georgieff, M. K., Crenshaw, T. D., and Kling, P. J. (2008). Reticulocyte enrichment of zinc protoporphyrin/heme discriminates impaired iron supply during early development. Pediatr. Res. 64, 63–67.
Reticulocyte enrichment of zinc protoporphyrin/heme discriminates impaired iron supply during early development.CrossRef | 1:CAS:528:DC%2BD1cXntFWntL4%3D&md5=f3016a3d9dadfe79a642e77e5b5d1c05CAS | 18360311PubMed | open url image1

Brenner, B. M., Garcia, D. L., and Anderson, S. (1988). Glomeruli and blood pressure: less of one, more the other? Am. J. Hypertens. 1, 335–347.
Glomeruli and blood pressure: less of one, more the other?CrossRef | 1:STN:280:DyaL1M7gsFegtA%3D%3D&md5=2576a85118dc9cee01d60e322779de95CAS | 3063284PubMed | open url image1

Brion, M. J., Leary, S. D., Smith, G. D., McArdle, H. J., and Ness, A. R. (2008). Maternal anemia, iron intake in pregnancy, and offspring blood pressure in the Avon Longitudinal Study of Parents and Children. Am. J. Clin. Nutr. 88, 1126–1133.
| 1:CAS:528:DC%2BD1cXht1Gks7bF&md5=68969b0ecd9e698231b66c371497e74fCAS | 18842803PubMed | open url image1

Chockalingam, U. M., Murphy, E., Ophoven, J. C., Weisdorf, S. A., and Georgieff, M. K. (1987). Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia. J. Pediatr. 111, 283–286.
Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufficiency and chronic hypoxia.CrossRef | 1:STN:280:DyaL2s3otlSnug%3D%3D&md5=234f28c02b4b2b92067dd5fc723854bbCAS | 3612404PubMed | open url image1

Drake, K. A., Sauerbry, M. J., Blohowiak, S. E., Repyak, K. S., and Kling, P. J. (2009). Iron deficiency and renal development in the newborn rat. Pediatr. Res. 66, 619–624.
Iron deficiency and renal development in the newborn rat.CrossRef | 1:CAS:528:DC%2BD1MXhsValu73I&md5=567bc0d3a3f762b3914d133269de500fCAS | 19730160PubMed | open url image1

Dunnill, M. S., and Halley, W. (1973). Some observations on the quantitative anatomy of the kidney. J. Pathol. 110, 113–121.
Some observations on the quantitative anatomy of the kidney.CrossRef | 1:STN:280:DyaE3s3ltFemug%3D%3D&md5=258d63e94ee8d10a506bd439f02fc903CAS | 4125872PubMed | open url image1

Feng, M., and DiPetrillo, K. (2009). Non-invasive blood pressure measurement in mice. Methods Mol. Biol. 573, 45–55.
Non-invasive blood pressure measurement in mice.CrossRef | 19763921PubMed | open url image1

Gambling, L., Dunford, S., Wallace, D. I., Zuur, G., Solanky, N., Srai, S. K., and McArdle, H. J. (2003). Iron deficiency during pregnancy affects postnatal blood pressure in the rat. J. Physiol. 552, 603–610.
Iron deficiency during pregnancy affects postnatal blood pressure in the rat.CrossRef | 1:CAS:528:DC%2BD3sXps1ehu78%3D&md5=22db8cf82c817857a809e03f27c73755CAS | 14561840PubMed | open url image1

Gambling, L., Czopek, A., Andersen, H. S., Holtrop, G., Srai, S. K., Krejpcio, Z., and McArdle, H. J. (2009). Fetal iron status regulates maternal iron metabolism during pregnancy in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R1063–R1070.
Fetal iron status regulates maternal iron metabolism during pregnancy in the rat.CrossRef | 1:CAS:528:DC%2BD1MXkvVygurY%3D&md5=534ea88d81f0f95d08254db0dc2cd9a5CAS | 19176888PubMed | open url image1

Georgieff, M. K., Mills, M. M., Gordon, K., and Wobken, J. D. (1995). Reduced neonatal liver iron concentrations after uteroplacental insufficiency. J. Pediatr. 127, 308–311.
Reduced neonatal liver iron concentrations after uteroplacental insufficiency.CrossRef | 1:CAS:528:DyaK2MXnsFGrsLY%3D&md5=8777e7e5a5604be42bcf0beb7d3b9798CAS | 7636662PubMed | open url image1

Godfrey, K. M., and Barker, D. J. (2000). Fetal nutrition and adult disease. Am. J. Clin. Nutr. 71, 1344S–1352S.
| 1:CAS:528:DC%2BD3cXivFymurY%3D&md5=da1e0e251df74b43f9c8d395851840c4CAS | 10799412PubMed | open url image1

Haycock, G. B. (1998). Development of glomerular filtration and tubular sodium reabsorption in the human fetus and newborn. Br. J. Urol. 81, 33–38.
Development of glomerular filtration and tubular sodium reabsorption in the human fetus and newborn.CrossRef | 9602793PubMed | open url image1

Hegde, N. V., Unger, E. L., Jensen, G. L., Hankey, P. L., and Paulson, R. F. (2011). Interrelationships between tissue iron status and erythropoiesis during postweaning development following neonatal iron deficiency in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G470–G476.
Interrelationships between tissue iron status and erythropoiesis during postweaning development following neonatal iron deficiency in rats.CrossRef | 1:CAS:528:DC%2BC3MXjs1Grt70%3D&md5=714afd76e0feeac08244ebdcb7461323CAS | 21193529PubMed | open url image1

Lewis, R. M., Forhead, A. J., Petry, C. J., Ozanne, S. E., and Hales, C. N. (2002). Long-term programming of blood pressure by maternal dietary iron restriction in the rat. Br. J. Nutr. 88, 283–290.
Long-term programming of blood pressure by maternal dietary iron restriction in the rat.CrossRef | 1:CAS:528:DC%2BD38XmvFCrsrs%3D&md5=301a2d90fa30c7defce01ddbe717164bCAS | 12207838PubMed | open url image1

Lisle, S. J., Lewis, R. M., Petry, C. J., Ozanne, S. E., Hales, C. N., and Forhead, A. J. (2003). Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring. Br. J. Nutr. 90, 33–39.
Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring.CrossRef | 1:CAS:528:DC%2BD3sXlslahsrk%3D&md5=88a91ac939d3044c595de0f6746b95f8CAS | 12844373PubMed | open url image1

Louey, S., Cock, M. L., Stevenson, K. M., and Harding, R. (2000). Placental insufficiency and fetal growth restriction lead to postnatal hypotension and altered postnatal growth in sheep. Pediatr. Res. 48, 808–814.
Placental insufficiency and fetal growth restriction lead to postnatal hypotension and altered postnatal growth in sheep.CrossRef | 1:STN:280:DC%2BD3M7hsVGrtQ%3D%3D&md5=4f64ab517ffc838957f9476cbf2eb8d1CAS | 11102551PubMed | open url image1

Lozoff, B., Kaciroti, N., and Walter, T. (2006). Iron deficiency in infancy: applying a physiologic framework for prediction. Am. J. Clin. Nutr. 84, 1412–1421.
| 1:CAS:528:DC%2BD28XhtlGrurjL&md5=51ec43c07e0c2f5fa8b2a17d19679500CAS | 17158425PubMed | open url image1

Mackenzie, H. S., and Brenner, B. M. (1995). Fewer nephrons at birth: a missing link in the etiology of essential hypertension? Am. J. Kidney Dis. 26, 91–98.
Fewer nephrons at birth: a missing link in the etiology of essential hypertension?CrossRef | 1:STN:280:DyaK2MzjsFKlsg%3D%3D&md5=652f14a40405a4aa6efa635dd33b1d5aCAS | 7611275PubMed | open url image1

McArdle, H. J., Gambling, L., and Kennedy, C. (2014). Iron deficiency during pregnancy: the consequences for placental function and fetal outcome. Proc. Nutr. Soc. 73, 9–15.
| 1:CAS:528:DC%2BC2cXitFyls7c%3D&md5=03f9b5297117edffffc9a4309cef0b99CAS | 24176079PubMed | open url image1

Miura, K., Nakagawa, H., Nakamura, H., Tabata, M., Nagase, H., Yoshida, M., and Okada, A. (1994). Serum creatinine level in predicting the development of hypertension. Ten-year follow-up of Japanese adults in a rural community. Am. J. Hypertens. 7, 390–395.
| 1:STN:280:DyaK2czjvVKhuw%3D%3D&md5=0f2432a146069413aec7de9349941517CAS | 8060570PubMed | open url image1

Moulouel, B., Houamel, D., Delaby, C., Tchernitchko, D., Vaulont, S., Letteron, P., Thibaudeau, O., Puy, H., Gouya, L., Beaumont, C., and Karim, Z. (2013). Hepcidin regulates intrarenal iron handling at the distal nephron. Kidney Int. 84, 756–766.
Hepcidin regulates intrarenal iron handling at the distal nephron.CrossRef | 1:CAS:528:DC%2BC3sXhsFOlt73O&md5=e07f9eb46f4de4f83409d997558ad110CAS | 23615502PubMed | open url image1

O’Brien, K. O., Zavaleta, N., Abrams, S. A., and Caulfield, L. E. (2003). Maternal iron status influences iron transfer to the fetus during the third trimester of pregnancy. Am. J. Clin. Nutr. 77, 924–930.
| 1:CAS:528:DC%2BD3sXnsVSrtrc%3D&md5=41618c25171ee04ca4b13a2697ceadcaCAS | 12663293PubMed | open url image1

Park, C. H., Valore, E. V., Waring, A. J., and Ganz, T. (2001). Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276, 7806–7810.
Hepcidin, a urinary antimicrobial peptide synthesized in the liver.CrossRef | 1:CAS:528:DC%2BD3MXitFKhtbo%3D&md5=3093caf83782e806ae2cc618ae1c00d4CAS | 11113131PubMed | open url image1

Pietrangelo, A. (2007). Hemochromatosis: an endocrine liver disease. Hepatology 46, 1291–1301.
Hemochromatosis: an endocrine liver disease.CrossRef | 1:CAS:528:DC%2BD2sXht1aksrvE&md5=edf3ca391b73271d3ca344c493acdaf5CAS | 17886335PubMed | open url image1

Rao, R., and Georgieff, M. K. (2002). Perinatal aspects of iron metabolism. Acta Paediatr. Suppl. 91, 124–129.
| 1:STN:280:DC%2BD38jhsV2huw%3D%3D&md5=7fd15fa1125242f6a49b7519eedbcb44CAS | 12477276PubMed | open url image1

Rao, R., and Georgieff, M. K. (2007). Iron in fetal and neonatal nutrition. Semin. Fetal Neonatal Med. 12, 54–63.
Iron in fetal and neonatal nutrition.CrossRef | 17157088PubMed | open url image1

Rao, R., Tkac, I., Townsend, E. L., Ennis, K., Gruetter, R., and Georgieff, M. K. (2007). Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia-ischemia. J. Cereb. Blood Flow Metab. 27, 729–740.
Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia-ischemia.CrossRef | 1:CAS:528:DC%2BD2sXkvFyntLk%3D&md5=5b82cc7c5a5c0bf143cf31995ff4626eCAS | 16868555PubMed | open url image1

Rao, R., Tkac, I., Unger, E. L., Ennis, K., Hurst, A., Schallert, T., Connor, J., Felt, B., and Georgieff, M. K. (2013). Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats. Pediatr. Res. 73, 31–37.
Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats.CrossRef | 1:CAS:528:DC%2BC3sXmslKguw%3D%3D&md5=0cec4b82396ff8a95114a7520c6ea8c5CAS | 23095980PubMed | open url image1

Rebouche, C. J., Wilcox, C. L., and Widness, J. A. (2004). Microanalysis of non-heme iron in animal tissues. J. Biochem. Biophys. Methods 58, 239–251.
Microanalysis of non-heme iron in animal tissues.CrossRef | 1:CAS:528:DC%2BD2cXitFChurg%3D&md5=99bc15178be1210860da3c168971221bCAS | 15026210PubMed | open url image1

Rodriguez, J. A., Vio, C. P., Pedraza, P. L., McGiff, J. C., and Ferreri, N. R. (2004). Bradykinin regulates cyclooxygenase-2 in rat renal thick ascending limb cells. Hypertension 44, 230–235.
Bradykinin regulates cyclooxygenase-2 in rat renal thick ascending limb cells.CrossRef | 1:CAS:528:DC%2BD2cXlvVKlsLc%3D&md5=582b2cf8673c5ae2df9fa1b949a8c571CAS | 15249543PubMed | open url image1

Rodriguez, M. M., Gomez, A., Abitbol, C., Chandar, J., Montane, B., and Zilleruelo, G. (2005). Comparative renal histomorphometry: a case study of oligonephropathy of prematurity. Pediatr. Nephrol. 20, 945–949.
Comparative renal histomorphometry: a case study of oligonephropathy of prematurity.CrossRef | 15856326PubMed | open url image1

Saxena, A. B., Myers, B. D., Derby, G., Blouch, K. L., Yan, J., Ho, B., and Tan, J. C. (2006). Adaptive hyperfiltration in the aging kidney after contralateral nephrectomy. Am. J. Physiol. Renal Physiol. 291, F629–F634.
Adaptive hyperfiltration in the aging kidney after contralateral nephrectomy.CrossRef | 1:CAS:528:DC%2BD28XhtVSks7nP&md5=b2efbd0f438d12b2a844b49f93a07db0CAS | 16525160PubMed | open url image1

Schillaci, G., Reboldi, G., and Verdecchia, P. (2001). High-normal serum creatinine concentration is a predictor of cardiovascular risk in essential hypertension. Arch. Intern. Med. 161, 886–891.
High-normal serum creatinine concentration is a predictor of cardiovascular risk in essential hypertension.CrossRef | 1:STN:280:DC%2BD3M3mtVektA%3D%3D&md5=fada691e296fb2050516e1ce62037c6bCAS | 11268234PubMed | open url image1

Scholl, T. O. (2005). Iron status during pregnancy: setting the stage for mother and infant. Am. J. Clin. Nutr. 81, 1218S–1222S.
| 1:CAS:528:DC%2BD2MXktlyks7s%3D&md5=1251aa398acd0fda1d2fed6c9ac39a8cCAS | 15883455PubMed | open url image1

Shah, M. M., Sampogna, R. V., Sakurai, H., Bush, K. T., and Nigam, S. K. (2004). Branching morphogenesis and kidney disease. Development 131, 1449–1462.
Branching morphogenesis and kidney disease.CrossRef | 1:CAS:528:DC%2BD2cXjsFKltLc%3D&md5=ca7c956d1e1d0c8c76df5ce25f171c32CAS | 15023929PubMed | open url image1

Siddappa, A. J., Rao, R. B., Wobken, J. D., Casperson, K., Leibold, E. A., Connor, J. R., and Georgieff, M. K. (2003). Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain. Pediatr. Res. 53, 800–807.
Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain.CrossRef | 1:CAS:528:DC%2BD3sXis12qtbc%3D&md5=87f22fd68d157bdd3e7dbd9b8babde22CAS | 12621119PubMed | open url image1

Smith, C. P., and Thevenod, F. (2009). Iron transport and the kidney. Biochim. Biophys. Acta 1790, 724–730.
Iron transport and the kidney.CrossRef | 1:CAS:528:DC%2BD1MXnt1yju7w%3D&md5=776b03f1d20956707179c9f854ace47eCAS | 19041692PubMed | open url image1

Stewart, T., Jung, F. F., Manning, J., and Vehaskari, V. M. (2005). Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension. Kidney Int. 68, 2180–2188.
Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension.CrossRef | 1:CAS:528:DC%2BD2MXht1SgtbbL&md5=736dbd9084097fc21b9eb8bf906bf815CAS | 16221217PubMed | open url image1

Sun, M. Y., Habeck, J. M., Meyer, K. M., Koch, J. M., Ramadoss, J., Blohowiak, S. E., Magness, R. R., and Kling, P. J. (2013). Ovine uterine space restriction alters placental transferrin receptor and fetal iron status during late pregnancy. Pediatr. Res. 73, 277–285.
Ovine uterine space restriction alters placental transferrin receptor and fetal iron status during late pregnancy.CrossRef | 1:CAS:528:DC%2BC3sXivFaqsb8%3D&md5=bab2364ac929888f00ac8604ccc820f4CAS | 23202722PubMed | open url image1

Tran, P. V., Fretham, S. J., Wobken, J., Miller, B. S., and Georgieff, M. K. (2012). Gestational–neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus. Am. J. Physiol. Endocrinol. Metab. 302, E316–E324.
Gestational–neonatal iron deficiency suppresses and iron treatment reactivates IGF signaling in developing rat hippocampus.CrossRef | 1:CAS:528:DC%2BC38XjsFKhu7w%3D&md5=07dd345b717af511d26d45a9b3cc1676CAS | 22068601PubMed | open url image1

Veuthey, T., Hoffmann, D., Vaidya, V. S., and Wessling-Resnick, M. (2014). Impaired renal function and development in Belgrade rats. Am. J. Physiol. Renal Physiol. 306, F333–F343.
Impaired renal function and development in Belgrade rats.CrossRef | 1:CAS:528:DC%2BC2cXjvFShsb8%3D&md5=f004d54f7ab4cce3500111dca03e5fa5CAS | 24226520PubMed | open url image1

Yeung, M. Y. (2006). Oligonephropathy, developmental programming and nutritional management of low-gestation newborns. Acta Paediatr. 95, 263–267.
Oligonephropathy, developmental programming and nutritional management of low-gestation newborns.CrossRef | 16497634PubMed | open url image1

Zohdi, V., Moritz, K. M., Bubb, K. J., Cock, M. L., Wreford, N., Harding, R., and Black, M. J. (2007). Nephrogenesis and the renal renin–angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1267–R1273.
Nephrogenesis and the renal renin–angiotensin system in fetal sheep: effects of intrauterine growth restriction during late gestation.CrossRef | 1:CAS:528:DC%2BD2sXhtVOqt7zK&md5=1925750d0498a862a6c88522091d6301CAS | 17581839PubMed | open url image1



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