Hostname: page-component-586b7cd67f-t8hqh Total loading time: 0 Render date: 2024-11-23T21:03:04.933Z Has data issue: false hasContentIssue false
  • English
  • Français

Maternal undernutrition upregulates apoptosis in offspring nephrogenesis

Published online by Cambridge University Press:  01 August 2011

S. A. Tafti ,
C. C. Nast ,
M. Desai ,
K. E. Amaya ,
M. G. Ross  and
T. R. Magee
S. A. Tafti
Affiliation:
Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, Torrance, CA, USA
C. C. Nast
Affiliation:
Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
M. Desai
Affiliation:
Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, Torrance, CA, USA Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
K. E. Amaya
Affiliation:
Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, Torrance, CA, USA
M. G. Ross
Affiliation:
Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, Torrance, CA, USA Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
T. R. Magee*
Affiliation:
Los Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, Torrance, CA, USA Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
*
*Address for correspondence: Dr T. Magee, Ph.D., Assistant Professor, LA BioMed, 1124 W. Carson Street, Building RB1, RM 215, Torrance, CA 90502, USA. (Email [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Maternal undernutrition (MUN) results in growth-restricted newborns with reduced nephron numbers that is associated with increased risk of hypertension and renal disease. The total adult complement of nephrons is set during nephrogenesis suggesting that MUN affects the staged development of nephrons in as yet unknown manner. A possible cause may be the increased renal apoptosis; therefore, we investigated whether apoptotic signaling and cell death were increased in MUN rat kidneys. Pregnant rat dams were fed an ad libitum diet [control] or were 50% food restricted (MUN) starting at embryonic day (E) 10. Male offspring kidneys (n = 5 each, MUN and control) were analyzed for mRNA using quantitative PCR (E20) and for protein expression using Western blotting and immunohistochemistry (E20 and postnatal day 1, P1). Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Upregulation of pro-apoptotic protein expression was detected at E20 (Fas receptor, caspase 9) and at P1 (caspase 3, Bax). The anti-apoptotic factor Bcl2 was significantly decreased in P1 kidneys. Kidney TUNEL showed apoptotic nuclei significantly increased in the P1 nephrogenic zone (MUN 3.3 + 0.3 v. C 1.6 + 0.5, P = 0.002). The majority of apoptotic nuclei co-localized to mesenchyme and pretubular aggregates in the nephrogenic zone. Differential regulation of apoptosis in mesenchyme and pretubular aggregates following parturition suggests a mechanism for nephropenia in gestational programming of the kidney.

Keywords

gestational programmingglomerulogenesishypertensionIUGRMUN
Type
Original Articles
Information
Journal of Developmental Origins of Health and Disease , Volume 2 , Issue 4 , August 2011 , pp. 226 - 235
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2011

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.)

Footnotes

a

Authors contributed equally to the work and are recognized as first co-authors.

References

1.Barker, DJ. The origins of the developmental origins theory. J Intern Med. 2007; 261, 412–417.CrossRefGoogle ScholarPubMed
2.Ross, MG, Beall, MH. Adult sequelae of intrauterine growth restriction. Semin Perinatol. 2008; 32, 213–218.CrossRefGoogle ScholarPubMed
3.Silver, LE, Decamps, PJ, Korst, LM, Platt, LD, Castro, LC. Intrauterine growth restriction is accompanied by decreased renal volume in the human fetus. Am J Obstet Gynecol. 2003; 188, 1320–1325.CrossRefGoogle ScholarPubMed
4.Latini, G, De, MB, Del, VA, et al. Foetal growth of kidneys, liver and spleen in intrauterine growth restriction: “programming” causing “metabolic syndrome” in adult age. Acta Paediatr. 2004; 93, 1635–1639.CrossRefGoogle Scholar
5.Moritz, KM, Wintour, EM. Functional development of the meso- and metanephros. Pediatr Nephrol. 1999; 13, 171–178.CrossRefGoogle ScholarPubMed
6.Henry, TQ, Mansano, RZ, Nast, CC, et al. GDNF and MAPK-ERK pathway signaling is reduced during nephrogenesis following maternal under-nutrition. J Dev Origins Health Disease. 2010; 1, 67–74.CrossRefGoogle ScholarPubMed
7.Ojeda, NB, Grigore, D, Alexander, BT. Intrauterine growth restriction: fetal programming of hypertension and kidney disease. Adv Chronic Kidney Dis. 2008; 15, 101–106.CrossRefGoogle ScholarPubMed
8.Schreuder, MF, Nyengaard, JR, Remmers, F, van Wijk, JA, Delemarre-van de Waal, HA. Postnatal food restriction in the rat as a model for a low nephron endowment. Am J Physiol Renal Physiol. 2006; 291, F1104–F1107.CrossRefGoogle Scholar
9.Pham, TD, MacLennan, NK, Chiu, CT, et al. 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, R962–R970.CrossRefGoogle ScholarPubMed
10.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, 252–257.CrossRefGoogle ScholarPubMed
11.Hida, M, Omori, S, Awazu, M. ERK and p38 MAP kinase are required for rat renal development. Kidney Int. 2002; 61, 1252–1262.CrossRefGoogle ScholarPubMed
12.Coles, HS, Burne, JF, Raff, MC. Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development. 1993; 118, 777–784.CrossRefGoogle ScholarPubMed
13.Okada, T, Iwamoto, A, Mukamoto, M, et al. Perinatal development of the rat kidney: apoptosis and epidermal growth factor. Congenit Anom (Kyoto). 2003; 43, 161–167.CrossRefGoogle ScholarPubMed
14.Sanz, AB, Santamaria, B, Ruiz-Ortega, M, Egido, J, Ortiz, A. Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol. 2008; 19, 1634–1642.CrossRefGoogle ScholarPubMed
15.Magee, TR, Tafti, SA, Desai, M, et al. Maternal undernourished fetal kidneys exhibit differential regulation of nephrogenic genes including downregulation of the Notch signaling pathway. Reprod Sci. 2011; 18, 563–576.CrossRefGoogle ScholarPubMed
16.Welham, SJ, Wade, A, Woolf, AS. Protein restriction in pregnancy is associated with increased apoptosis of mesenchymal cells at the start of rat metanephrogenesis. Kidney Int. 2002; 61, 1231–1242.CrossRefGoogle ScholarPubMed
17.Gilbert, JS, Nijland, MJ. Sex differences in the developmental origins of hypertension and cardiorenal disease. Am J Physiol Regul Integr Comp Physiol. 2008; 295, R1941–R1952.CrossRefGoogle ScholarPubMed
18.Ozaki, T, Nishina, H, Hanson, MA, Poston, L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol. 2001; 530, 141–152.CrossRefGoogle ScholarPubMed
19.Brawley, L, Itoh, S, Torrens, C, et al. Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr Res. 2003; 54, 83–90.CrossRefGoogle ScholarPubMed
20.Woods, LL, Ingelfinger, JR, Rasch, R. Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol. 2005; 289, R1131–R1136.CrossRefGoogle ScholarPubMed
21.Livak, KJ, Schmittgen, TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001; 25, 402–408.CrossRefGoogle ScholarPubMed
22.Choi, GY, Tosh, DN, Garg, A, et al. Gender-specific programmed hepatic lipid dysregulation in intrauterine growth-restricted offspring. Am J Obstet Gynecol. 2007; 196, 477–477.CrossRefGoogle ScholarPubMed
23.Georgas, K, Rumballe, B, Wilkinson, L, et al. Use of dual section mRNA in situ hybridisation/immunohistochemistry to clarify gene expression patterns during the early stages of nephron development in the embryo and in the mature nephron of the adult mouse kidney. Histochem Cell Biol. 2008; 130, 927–942.CrossRefGoogle ScholarPubMed
24.Desai, M, Gayle, D, Babu, J, Ross, MG. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005; 288, R91–R96.CrossRefGoogle ScholarPubMed
25.Jelks, A, Belkacemi, L, Han, G, et al. Paradoxical increase in maternal plasma leptin levels in food-restricted gestation: contribution by placental and adipose tissue. Reprod Sci. 2009; 16, 665–675.CrossRefGoogle ScholarPubMed
26.Schreuder, MF, Nauta, J. Prenatal programming of nephron number and blood pressure. Kidney Int. 2007; 72, 265–268.CrossRefGoogle ScholarPubMed
27.do Carmo Pinho Franco, M, Nigro, D, Fortes, ZB, et al. Intrauterine undernutrition–renal and vascular origin of hypertension. Cardiovasc Res. 2003; 60, 228–234.CrossRefGoogle ScholarPubMed
28.Fowden, AL, Giussani, DA, Forhead, AJ. Intrauterine programming of physiological systems: causes and consequences. Physiology (Bethesda). 2006; 21, 29–37.Google ScholarPubMed
29.Welham, SJ, Riley, PR, Wade, A, Hubank, M, Woolf, AS. Maternal diet programs embryonic kidney gene expression. Physiol Genomics. 2005; 22, 48–56.CrossRefGoogle ScholarPubMed
30.Koseki, C, Herzlinger, D, Al-Awqati, Q. Apoptosis in metanephric development. J Cell Biol. 1992; 119, 1327–1333.CrossRefGoogle ScholarPubMed
31.Foley, JG, Bard, JB. Apoptosis in the cortex of the developing mouse kidney. J Anat. 2002; 201, 477–484.CrossRefGoogle ScholarPubMed
32.Hartman, HA, Lai, HL, Patterson, LT. Cessation of renal morphogenesis in mice. Dev Biol. 2007; 310, 379–387.CrossRefGoogle ScholarPubMed
33.Wlodek, ME, Mibus, A, Tan, A, et al. Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat. J Am Soc Nephrol. 2007; 18, 1688–1696.CrossRefGoogle ScholarPubMed
34.Carev, D, Krnic, D, Saraga, M, Sapunar, D, Saraga-Babic, M. Role of mitotic, pro-apoptotic and anti-apoptotic factors in human kidney development. Pediatr Nephrol. 2006; 21, 627–636.CrossRefGoogle ScholarPubMed
35.Wajant, H. The Fas signaling pathway: more than a paradigm. Science. 2002; 296, 1635–1636.CrossRefGoogle ScholarPubMed
36.Jones, NL, Day, AS, Jennings, HA, Sherman, PM. Helicobacter pylori induces gastric epithelial cell apoptosis in association with increased Fas receptor expression. Infect Immun. 1999; 67, 4237–4242.CrossRefGoogle ScholarPubMed
37.Muschen, M, Warskulat, U, Douillard, P, Gilbert, E, Haussinger, D. Regulation of CD95 (APO-1/Fas) receptor and ligand expression by lipopolysaccharide and dexamethasone in parenchymal and nonparenchymal rat liver cells. Hepatology. 1998; 27, 200–208.CrossRefGoogle ScholarPubMed
38.Sorenson, CM, Rogers, SA, Korsmeyer, SJ, Hammerman, MR. Fulminant metanephric apoptosis and abnormal kidney development in bcl-2-deficient mice. Am J Physiol. 1995; 268, F73–F81.Google ScholarPubMed
39.Liu, WH, Hsiao, HW, Tsou, WI, Lai, MZ. Notch inhibits apoptosis by direct interference with XIAP ubiquitination and degradation. EMBO J. 2007; 26, 1660–1669.CrossRefGoogle ScholarPubMed
40.Duechler, M, Shehata, M, Schwarzmeier, JD, et al. Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2. Leukemia. 2005; 19, 260–267.CrossRefGoogle ScholarPubMed