Hostname: page-component-745bb68f8f-mzp66 Total loading time: 0 Render date: 2025-01-23T14:43:00.068Z Has data issue: false hasContentIssue false
  • English
  • Français

Epigenetic mechanisms involved in intrauterine growth restriction and aberrant kidney development and function

Published online by Cambridge University Press:  22 December 2020

Thu N. A. Doan ,
Jessica F. Briffa ,
Aaron L. Phillips ,
Shalem Y. Leemaqz ,
Rachel A. Burton ,
Tania Romano Open the ORCID record for Tania Romano [Opens in a new window] ,
Mary E. Wlodek  and
Tina Bianco-Miotto Open the ORCID record for Tina Bianco-Miotto [Opens in a new window]
Thu N. A. Doan
Affiliation:
School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Adelaide, South Australia, Australia Robinson Research Institute, University of Adelaide, South Australia, Australia
Jessica F. Briffa
Affiliation:
Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia
Aaron L. Phillips
Affiliation:
School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Adelaide, South Australia, Australia
Shalem Y. Leemaqz
Affiliation:
Robinson Research Institute, University of Adelaide, South Australia, Australia South Australian Health & Medical Research Institute, SAHMRI Women and Kids, Adelaide, Australia College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
Rachel A. Burton
Affiliation:
School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Adelaide, South Australia, Australia
Tania Romano
Affiliation:
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
Mary E. Wlodek
Affiliation:
Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia
Tina Bianco-Miotto*
Affiliation:
School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Adelaide, South Australia, Australia Robinson Research Institute, University of Adelaide, South Australia, Australia
*
Address for correspondence:*Tina Bianco-Miotto, School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Adelaide, South Australia, Australia. Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Intrauterine growth restriction (IUGR) due to uteroplacental insufficiency results in a placenta that is unable to provide adequate nutrients and oxygen to the fetus. These growth-restricted babies have an increased risk of hypertension and chronic kidney disease later in life. In rats, both male and female growth-restricted offspring have nephron deficits but only males develop kidney dysfunction and high blood pressure. In addition, there is transgenerational transmission of nephron deficits and hypertension risk. Therefore, epigenetic mechanisms may explain the sex-specific programming and multigenerational transmission of IUGR-related phenotypes. Expression of DNA methyltransferases (Dnmt1and Dnmt3a) and imprinted genes (Peg3, Snrpn, Kcnq1, and Cdkn1c) were investigated in kidney tissues of sham and IUGR rats in F1 (embryonic day 20 (E20) and postnatal day 1 (PN1)) and F2 (6 and 12 months of age, paternal and maternal lines) generations (n = 6–13/group). In comparison to sham offspring, F1 IUGR rats had a 19% decrease in Dnmt3a expression at E20 (P < 0.05), with decreased Cdkn1c (19%, P < 0.05) and increased Kcnq1 (1.6-fold, P < 0.01) at PN1. There was a sex-specific difference in Cdkn1c and Snrpn expression at E20, with 29% and 34% higher expression in IUGR males compared to females, respectively (P < 0.05). Peg3 sex-specific expression was lost in the F2 IUGR offspring, only in the maternal line. These findings suggest that epigenetic mechanisms may be altered in renal embryonic and/or fetal development in growth-restricted offspring, which could alter kidney function, predisposing these offspring to kidney disease later in life.

Keywords

Intrauterine growth restrictionuteroplacental insufficiencykidneyfetal developmentimprinted genes
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 6 , December 2021 , pp. 952 - 962
Copyright
© The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Luyckx, VA, Brenner, BM. Low birth weight, nephron number, and kidney disease. Kidney Int. 2005; 68, S68–S77.CrossRefGoogle Scholar
Lee, AC, Kozuki, N, Cousens, S, et al. Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets. BMJ. 2017; 358, j4229.Google ScholarPubMed
Australian-Institute-of-Health-and-Welfare. Australia’s Mothers and Babies Data Visualisations, 2019. AIHW, Canberra.Google Scholar
Barker, DJP. The developmental origins of adult disease. J Am Coll Nutr. 2004; 23(Suppl 6), 588S–595S.CrossRefGoogle ScholarPubMed
Spence, D, Stewart, MC, Alderdice, FA, Patterson, CC, Halliday, HL. Intra-uterine growth restriction and increased risk of hypertension in adult life: a follow-up study of 50-year-olds. Public Health. 2012; 126(7), 561–565.10.1016/j.puhe.2012.03.010CrossRefGoogle ScholarPubMed
Shankaran, S, Das, A, Bauer, CR, et al. Fetal origin of childhood disease: intrauterine growth restriction in term infants and risk for hypertension at 6 years of age. Arch Pediatr Adolesc Med. 2006; 160(9), 977–981.10.1001/archpedi.160.9.977CrossRefGoogle ScholarPubMed
Wang, YP, Chen, X, Zhang, ZK, Cui, HY, Wang, P, Wang, Y. Effects of a restricted fetal growth environment on human kidney morphology, cell apoptosis and gene expression. J Renin Angiotensin Aldosterone Syst. 2014; 16(4), 1028–1035.CrossRefGoogle ScholarPubMed
Keller, G, Zimmer, G, Mall, G, Ritz, E, Amann, K. Nephron number in patients with primary hypertension. N Engl J Med. 2003; 348(2), 101–108.CrossRefGoogle ScholarPubMed
Hughson, MD, Douglas, DR, Bertram, JF, Hoy, WE. Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States. Kidney Int. 2006; 69(4), 671–678.CrossRefGoogle ScholarPubMed
Moritz, KM, Mazzuca, MQ, Siebel, AL, et al. Uteroplacental insufficiency causes a nephron deficit, modest renal insufficiency but no hypertension with ageing in female rats. J Physiol. 2009; 587(Pt 11), 2635–2646.CrossRefGoogle ScholarPubMed
Alexander, BT. Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension. 2003; 41(3), 457.CrossRefGoogle ScholarPubMed
Bassan, H, Leider, TL, Kariv, N, et al. Experimental intrauterine growth retardation alters renal development. Pediatr Nephrol. 2000; 15(3), 192–195.CrossRefGoogle ScholarPubMed
Briscoe, TA, Rehn, AE, Dieni, S, et al. Cardiovascular and renal disease in the adolescent guinea pig after chronic placental insufficiency. Am J Obstet Gynecol. 2004; 191(3), 847–855.CrossRefGoogle ScholarPubMed
Wlodek, ME, Westcott, K, Siebel, AL, Owens, JA, Moritz, KM. Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats. Kidney Int. 2008; 74(2), 187–195.CrossRefGoogle ScholarPubMed
Cuffe, JSM, Briffa, JF, Rosser, S, et al. Uteroplacental insufficiency in rats induces renal apoptosis and delays nephrogenesis completion. Acta Physiologica. 2018; 222(3), e12982.CrossRefGoogle ScholarPubMed
Melanie, T, Linda, AG, Andrew, JJ, Karen, MM, Mary, EW. Transgenerational metabolic outcomes associated with uteroplacental insufficiency. J Endocrinol. 2013; 217(1), 105–118.Google Scholar
Gallo, LA, Tran, M, Cullen-McEwen, LA, et al. Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats. Reprod Fertil Dev. 2014; 26(7), 1032–1043.CrossRefGoogle ScholarPubMed
Master, JS, Zimanyi, MA, Yin, KV, et al. Transgenerational left ventricular hypertrophy and hypertension in offspring after uteroplacental insufficiency in male rats. Clin Exp Pharmacol Physiol. 2014; 41(11), 884–890.CrossRefGoogle ScholarPubMed
Baserga, M, Bares, AL, Hale, MA, et al. Uteroplacental insufficiency affects kidney VEGF expression in a model of IUGR with compensatory glomerular hypertrophy and hypertension. Early Hum Dev. 2009; 85(6), 361–367.CrossRefGoogle Scholar
Styrud, J, Eriksson, UJ, Grill, V, Swenne, I. Experimental intrauterine growth retardation in the rat causes a reduction of pancreatic B-cell mass, which persists into adulthood. Neonatology. 2005; 88(2), 122–128.CrossRefGoogle ScholarPubMed
Briffa, JF, Wlodek, ME, Moritz, KM. Transgenerational programming of nephron deficits and hypertension. Semin Cell Dev Biol. 2018; 103(17), 30447–30440.Google ScholarPubMed
Gonzalez-Rodriguez, P, Cantu, J, O’Neil, D, et al. Alterations in expression of imprinted genes from the H19/Igf2 loci in a multigenerational model of intrauterine growth restriction (IUGR). Am J Obstet Gynecol. 2016; 214(5), 625.e621–-625.e611.Google Scholar
Temple, IK, Gardner, RJ, Robinson, DO, et al. Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22–q23. Hum Mol Genet. 1996; 5(8), 1117–1121.CrossRefGoogle ScholarPubMed
Azzi, S, Rossignol, S, Steunou, V, et al. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet. 2009; 18(24), 4724–4733.10.1093/hmg/ddp435CrossRefGoogle Scholar
Arima, T, Kamikihara, T, Hayashida, T, et al. ZAC, LIT1 (KCNQ1OT1) and p57 KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith–Wiedemann syndrome. Nucleic Acids Res. 2005; 33(8), 2650–2660.CrossRefGoogle Scholar
Bliek, J, Verde, G, Callaway, J, et al. Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome. Eur J Hum Genet. 2009; 17(5), 611–619.CrossRefGoogle ScholarPubMed
Ke, X, Lei, Q, James, SJ, et al. Uteroplacental insufficiency affects epigenetic determinants of chromatin structure in brains of neonatal and juvenile IUGR rats. Physiol Genomics. 2006; 25(1), 16–28.CrossRefGoogle ScholarPubMed
Martínez, D, Pentinat, T, Ribó, S, et al. In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell Metab. 2014; 19(6), 941–951.CrossRefGoogle ScholarPubMed
Park, JH, Stoffers, DA, Nicholls, RD, Simmons, RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1 . J Clin Invest. 2008; 118(6), 2316–2324.Google ScholarPubMed
Mangwiro, YTM, Cuffe, JSM, Mahizir, D, et al. Exercise initiated during pregnancy in rats born growth restricted alters placental mTOR and nutrient transporter expression. J Physiol. 2019; 597(7), 1905–1918.CrossRefGoogle ScholarPubMed
Briffa, JF, O’Dowd, R, Moritz, KM, et al. Uteroplacental insufficiency reduces rat plasma leptin concentrations and alters placental leptin transporters: ameliorated with enhanced milk intake and nutrition. J Physiol. 2017; 595(11), 3389–3407.CrossRefGoogle ScholarPubMed
Hellemans, J, Mortier, G, De Paepe, A, Speleman, F, Vandesompele, J. qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 2007; 8(2), R19–R19.CrossRefGoogle ScholarPubMed
R Core Team. R: A Language and Environment for Statistical Computing, 2018. R Foundation for Statistical Computing, Vienna, Austria.Google Scholar
RStudio Team. RStudio: Integrated Development for R, 2020. RStudio, PBC, Boston, MA.Google Scholar
Stampone, E, Caldarelli, I, Zullo, A, et al. Genetic and epigenetic control of CDKN1C expression: importance in cell commitment and differentiation, tissue homeostasis and human diseases. Int J Mol Sci. 2018; 19(4), 1055.CrossRefGoogle ScholarPubMed
Dekel, B, Metsuyanim, S, Schmidt-Ott, KM, et al. Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney. Cancer Res. 2006; 66(12), 6040.CrossRefGoogle ScholarPubMed
Algar, EM, Muscat, A, Dagar, V, et al. Imprinted CDKN1C is a tumor suppressor in rhabdoid tumor and activated by restoration of SMARCB1 and histone deacetylase inhibitors. PLoS One. 2009; 4(2), e4482–e4482.CrossRefGoogle ScholarPubMed
Zhan, Q, Qi, X, Wang, N, et al. Altered methylations of H19, Snrpn, Mest and Peg3 are reversible by developmental reprogramming in kidney tissue of ICSI-derived mice. Sci Rep. 2017; 7(1), 11936.CrossRefGoogle ScholarPubMed
Jespersen, T, Grunnet, M, Olesen, S-P. The KCNQ1 potassium channel: from gene to physiological function. Physiology. 2005; 20(6), 408–416.CrossRefGoogle ScholarPubMed
Zheng, W, Verlander, JW, Lynch, IJ, et al. Cellular distribution of the potassium channel KCNQ1 in normal mouse kidney. Am J Physiol Renal Physiol. 2007; 292(1), F456–F466.CrossRefGoogle ScholarPubMed
Heijmans, BT, Tobi, EW, Stein, AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci. 2008; 105(44), 17046–17049.CrossRefGoogle ScholarPubMed
Einstein, F, Thompson, RF, Bhagat, TD, et al. Cytosine methylation dysregulation in neonates following intrauterine growth restriction. PLoS One. 2010; 5(1), e8887.CrossRefGoogle ScholarPubMed
Hillman, SL, Finer, S, Smart, MC, et al. Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates. Epigenetics. 2015; 10(1), 1–12.CrossRefGoogle ScholarPubMed
Novielli, C, Mandò, C, Tabano, S, et al. Mitochondrial DNA content and methylation in fetal cord blood of pregnancies with placental insufficiency. Placenta. 2017; 55, 63–70.CrossRefGoogle ScholarPubMed
Pham, TD, MacLennan, NK, Chiu, CT, Laksana, GS, Hsu, JL, Lane, RH. Uteroplacental insufficiency increases apoptosis and alters p53 gene methylation in the full-term IUGR rat kidney. Am J Physiol Regul Integr Comp Physiol. 2003; 285(5), R962–R970.CrossRefGoogle ScholarPubMed
Thompson, RF, Fazzari, MJ, Niu, H, Barzilai, N, Simmons, R, Greally, JM. Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats. J Biol Chem. 2010; 285, 15111–15118.CrossRefGoogle ScholarPubMed
Fujioka, K, Nishida, K, Ashina, M, et al. DNA methylation of the Rtl1 promoter in the placentas with fetal growth restriction. Pediatr Neonatol. 2019; 60(5), 512–516.CrossRefGoogle ScholarPubMed
Wanner, N, Vornweg, J, Combes, A, et al. DNA methyltransferase 1 controls nephron progenitor cell renewal and differentiation. J Am Soc Nephrol. 2019; 30(1), 63.CrossRefGoogle ScholarPubMed
Yang, SM, Huang, CY, Shiue, HS, et al. Combined effects of DNA methyltransferase 1 and 3A polymorphisms and urinary total arsenic levels on the risk for clear cell renal cell carcinoma. Toxicol Appl Pharmacol. 2016; 305, 103–110.CrossRefGoogle ScholarPubMed
Watanabe, D, Suetake, I, Tada, T, Tajima, S. Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mech Dev. 2002; 118(1), 187–190.10.1016/S0925-4773(02)00242-3CrossRefGoogle ScholarPubMed
Seely, JC. A brief review of kidney development, maturation, developmental abnormalities, and drug toxicity: juvenile animal relevancy. J Toxicol Pathol. 2017; 30(2), 125–133.CrossRefGoogle ScholarPubMed
Abdel-Hakeem, AK, Henry, TQ, Magee, TR, et al. Mechanisms of impaired nephrogenesis with fetal growth restriction: altered renal transcription and growth factor expression. Am J Obstet Gynecol. 2008; 199(3), 252.e251–252.e2527.CrossRefGoogle ScholarPubMed
Kaneda, M, Okano, M, Hata, K, et al. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 2004; 429(6994), 900–903.CrossRefGoogle Scholar
Peña, JC, Monk, C, Champagne, AF. Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLoS One. 2012; 6(7), e39791.CrossRefGoogle Scholar
De-Crescenzo, A, Sparago, A, Cerrato, F, et al. Paternal deletion of the 11p15.5 centromeric-imprinting control region is associated with alteration of imprinted gene expression and recurrent severe intrauterine growth restriction. J Med Genet. 2013; 50(2), 99.10.1136/jmedgenet-2012-101352CrossRefGoogle ScholarPubMed
Cordeiro, A, Neto, AP, Carvalho, F, Ramalho, C, Dória, S. Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes. J Assist Reprod Genet. 2014; 31(10), 1361–1368.CrossRefGoogle ScholarPubMed
Baserga, M, Hale, MA, Wang, ZM, et al. Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension. Am J Physiol Regul Integr Comp Physiol. 2007; 292(5), R1943–R1955.CrossRefGoogle Scholar
Baserga, M, Kaur, R, Hale, MA, et al. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11β-hydroxysteroid dehydrogenase type 2 in a sex-specific manner. Am J Physiol Regul Integr Comp Physiol. 2010; 299(1), R334–R342.CrossRefGoogle Scholar
Schwienbacher, C, Angioni, A, Scelfo, R, et al. Abnormal RNA expression of 11p15 imprinted genes and kidney developmental genes in Wilms’ tumor. Cancer Res. 2000; 60(6), 1521.Google ScholarPubMed
Gadd, S, Sredni, ST, Huang, C-C, Perlman, EJ. Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab Invest. 2010; 90(5), 724.CrossRefGoogle ScholarPubMed
Xu, P, Wu, Z, Yang, W, Wang, L. Dysregulation of DNA methylation and expression of imprinted genes in mouse placentas of fetal growth restriction induced by maternal cadmium exposure. Toxicology. 2017; 390, 109–116.CrossRefGoogle ScholarPubMed
Gou, C, Liu, X, Shi, X, et al. Placental expressions of CDKN1C and KCNQ1OT1 in monozygotic twins with selective intrauterine growth restriction. Twin Res Human Genet. 2017; 20(5), 389–394.CrossRefGoogle ScholarPubMed
Chen, XJ, Chen, F, Lv, PP, et al. Maternal high estradiol exposure alters CDKN1C and IGF2 expression in human placenta. Placenta. 2018; 61, 72–79.CrossRefGoogle ScholarPubMed
Saha, P, Verma, S, Pathak, RU, Mishra, RK. Long noncoding RNAs in mammalian development and diseases. Adv Exp Med Biol. 2017; 1008, 155–198.CrossRefGoogle ScholarPubMed
Bhogal, B, Arnaudo, A, Dymkowski, A, Best, A, Davis, TL. Methylation at mouse Cdkn1c is acquired during postimplantation development and functions to maintain imprinted expression. Genomics. 2004; 84(6), 961–970.CrossRefGoogle ScholarPubMed
Fitzpatrick, GV, Soloway, PD, Higgins, MJ. Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1. Nat Genet. 2002; 32(3), 426–431.CrossRefGoogle ScholarPubMed
Mancini-Dinardo, D, Steele, SJS, Levorse, JM, Ingram, RS, Tilghman, SM. Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes. Genes Dev. 2006; 20(10), 1268–1282.CrossRefGoogle ScholarPubMed
Miyazaki, K, Mapendano, CK, Fuchigami, T, et al. Developmentally dynamic changes of DNA methylation in the mouse Snurf/Snrpn gene. Gene. 2009; 432(1), 97–101.CrossRefGoogle ScholarPubMed
Diplas, AI, Lambertini, L, Lee, MJ, et al. Differential expression of imprinted genes in normal and IUGR human placentas. Epigenetics. 2009; 4(4), 235–240.CrossRefGoogle ScholarPubMed
Bourque, DK, Avila, L, Peñaherrera, M, von Dadelszen, P, Robinson, WP. Decreased placental methylation at the H19/IGF2 imprinting control region is associated with normotensive intrauterine growth restriction but not preeclampsia. Placenta. 2010; 31(3), 197–202.CrossRefGoogle Scholar
Li, B, Chen, S, Tang, N, et al. Assisted reproduction causes reduced fetal growth associated with downregulation of paternally expressed imprinted genes that enhance fetal growth in mice. Biol Reprod. 2016; 94(2), 45.CrossRefGoogle ScholarPubMed
Supplementary material: File

Doan et al. supplementary material

Figures S1-S3 and Tables S1-S3

Download Doan et al. supplementary material(File)
File 837.7 KB