Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-25T07:17:44.245Z Has data issue: false hasContentIssue false
  • English
  • Français

GDNF and MAPK–ERK pathway signaling is reduced during nephrogenesis following maternal under-nutrition

Published online by Cambridge University Press:  09 December 2009

T. Q. Henry ,
R. Z. Mansano ,
C. C. Nast ,
J. Lakshmanan ,
M. Abdallah ,
A. K. Abdel-Hakeem ,
M. Desai ,
M. G. Ross  and
T. R. Magee
T. Q. Henry
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
R. Z. Mansano
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
C. C. Nast
Affiliation:
Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
J. Lakshmanan
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
M. Abdallah
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
A. K. Abdel-Hakeem
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
M. Desai
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
M. G. Ross
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
T. R. Magee*
Affiliation:
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, and Los Angeles Biomedical Research Institute, Harbor–UCLA Medical Center, Torrance, CA, USA
*
Address for correspondence: T. R. Magee, Assistant Professor, 1124 W. Carson St Building RB1, RM 215, Torrance, CA 90502, USA. (Emails [email protected], [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Maternal under-nutrition (MUN) during gestation results in growth-restricted newborns with reduced glomerular number and subsequent hypertension. We investigated dysregulation of glial derived neurotrophic factor (GDNF) and MAPK–ERK (mitogen-activated protein kinase–extracellular signal-regulated protein kinase) signal pathway gene expression following MUN. MUN rats were 50% food restricted from embryonic day 10 till postnatal day 1. Kidneys were harvested at embryonic day (E)20, and postnatal days (P)1 and 21. Kidney protein expression was determined by Western blot. At E20, protein expression of growth factor receptor alpha 1 (GFRα1) and phosphorylated ERK1/2 and mitogen-activated protein kinase kinase (MEK)1/2 were reduced significantly, and immunohistochemistry confirmed reduction of phosphorylated ERK (pERK) with maintenance of pERK localization. Total MEK and ERK were unchanged. At P1, only GFRα1 and pERK1/2 were reduced significantly while at P21, expression of all growth factors except total MEK was unchanged. Total MEK was increased. Glomerular number was decreased by 19% in P21 kidneys and blood pressure was increased in 12-week-old rats. In conclusion, GDNF and MAPK–ERK signaling are dysregulated during active nephrogenesis in fetal and early newborn offspring kidneys in the MUN model. This may be a key mechanism in reduced offspring nephrogenesis and programmed hypertension.

Keywords

ERK signaling, gestational programming, maternal under-nutrition, nephrogenesis, nephropenia
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 1 , Issue 1 , February 2010 , pp. 67 - 74
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2009

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

1.Brenner, BM, Chertow, GM. Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis. 1994; 23, 171–175.CrossRefGoogle ScholarPubMed
2.Barker, DJ. The malnourished baby and infant. Br Med Bull. 2001; 60, 69–88.CrossRefGoogle ScholarPubMed
3.Hales, CN, Barker, DJ. The thrifty phenotype hypothesis. Br Med Bull. 2001; 60, 5–20.CrossRefGoogle ScholarPubMed
4.Phillips, DI, Jones, A, Goulden, PA. Birth weight, stress, and the metabolic syndrome in adult life. Ann N Y Acad Sci. 2006; 1083, 28–36.CrossRefGoogle ScholarPubMed
5.Barker, DJ. Fetal programming of coronary heart disease. Trends Endocrinol Metab. 2002; 13, 364–368.Google Scholar
6.Holemans, K, Aerts, L, Van Assche, FA. Fetal growth restriction and consequences for the offspring in animal models. J Soc Gynecol Investig. 2003; 10, 392–399.Google Scholar
7.Desai, M, Babu, J, Ross, MG. Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition. Am J Physiol Regul Integr Comp Physiol. 2007; 293, R2306–R2314.CrossRefGoogle ScholarPubMed
8.Simmons, RA, Gounis, AS, Bangalore, SA, Ogata, ES. Intrauterine growth retardation: fetal glucose transport is diminished in lung but spared in brain. Pediatr Res. 1992; 31, 59–63.Google Scholar
9.Schreuder, MF, Nauta, J. Prenatal programming of nephron number and blood pressure. Kidney Int. 2007; 72, 265–268.CrossRefGoogle ScholarPubMed
10.Bagby, SP. Maternal nutrition, low nephron number, and hypertension in later life: pathways of nutritional programming. J Nutr. 2007; 137, 1066–1072.Google Scholar
11.Barker, DJ, Bagby, SP, Hanson, MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol. 2006; 2, 700–707.CrossRefGoogle ScholarPubMed
12.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
13.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
14.Chen, CM, Chou, HC. Effects of maternal undernutrition on glomerular ultrastructure in rat offspring. Pediatr Neonatol. 2009; 50, 50–53.CrossRefGoogle ScholarPubMed
15.Brenner, BM, Mackenzie, HS. Nephron mass as a risk factor for progression of renal disease. Kidney Int Suppl. 1997; 63, S124–S127.Google ScholarPubMed
16.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.Google Scholar
17.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
18.Fowden, AL, Giussani, DA, Forhead, AJ. Intrauterine programming of physiological systems: causes and consequences. Physiology (Bethesda). 2006; 21, 29–37.Google Scholar
19.Pichel, JG, Shen, L, Sheng, HZ, et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996; 382, 73–76.Google Scholar
20.Cullen-McEwen, LA, Drago, J, Bertram, JF. Nephron endowment in glial cell line-derived neurotrophic factor (GDNF) heterozygous mice. Kidney Int. 2001; 60, 31–36.CrossRefGoogle ScholarPubMed
21.Zhang, Z, Quinlan, J, Hoy, W, et al. A common RET variant is associated with reduced newborn kidney size and function. J Am Soc Nephrol. 2008; 19, 2027–2034.CrossRefGoogle ScholarPubMed
22.Shah, MM, Sampogna, RV, Sakurai, H, Bush, KT, Nigam, SK. Branching morphogenesis and kidney disease. Development. 2004; 131, 1449–1462.Google Scholar
23.Durbec, P, Marcos-Gutierrez, CV, Kilkenny, C, et al. GDNF signaling through the Ret receptor tyrosine kinase. Nature. 1996; 381, 789–793.Google Scholar
24.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.Google Scholar
25.Hida, M, Omori, S, Awazu, M. ERK and p38 MAP kinase are required for rat renal development. Kidney Int. 2002; 61, 1252–1262.Google Scholar
26.Fisher, CE, Michael, L, Barnett, MW, Davies, JA. Erk MAP kinase regulates branching morphogenesis in the developing mouse kidney. Development. 2001; 128, 4329–4338.Google Scholar
27.Tang, MJ, Cai, Y, Tsai, SJ, Wang, YK, Dressler, GR. Ureteric bud outgrowth in response to RET activation is mediated by phosphatidylinositol 3-kinase. Dev Biol. 2002; 243, 128–136.CrossRefGoogle ScholarPubMed
28.Mansano, R, Desai, M, Garg, A, Choi, GY, Ross, MG. Enhanced nephrogenesis in offspring of water-restricted rat dams. Am J Obstet Gynecol. 2007; 196, 480–486.CrossRefGoogle ScholarPubMed
29.Choi, GY, Tosh, DN, Garg, A, et al. Gender-specific programmed hepatic lipid deregulation in intrauterine growth-restricted offspring. Am J Obstet Gynecol. 2007; 196, 477–477.Google Scholar
30.Cantini, LP, Ferrini, MG, Vernet, D, et al. Profibrotic role of myostatin in Peyronie’s disease. J Sex Med. 2008; 5, 1607–1622.Google Scholar
31.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.Google Scholar
32.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.Google Scholar
33.Popsueva, A, Poteryaev, D, Arighi, E, et al. GDNF promotes tubulogenesis of GFRalpha1 expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase. J Cell Biol. 2003; 161, 119–129.CrossRefGoogle ScholarPubMed
34.Tsigelny, IF, Kouznetsova, VL, Sweeney, DE, et al. Analysis of metagene portraits reveals distinct transitions during kidney organogenesis. Sci Signal. 2008; 1, ra16.CrossRefGoogle ScholarPubMed
35.Orth, SR, Ritz, E, Suter-Crazzolara, C. Glial cell line-derived neurotrophic factor (GDNF) is expressed in the human kidney and is a growth factor for human mesangial cells. Nephrol Dial Transplant. 2000; 15, 589–595.Google Scholar
36.Cullen-McEwen, LA, Kett, MM, Dowling, J, Anderson, WP, Bertram, JF. Nephron number, renal function, and arterial pressure in aged GDNF heterozygous mice. Hypertension. 2003; 41, 335–340.CrossRefGoogle ScholarPubMed
37.Vega, QC, Worby, CA, Lechner, MS, Dixon, JE, Dressler, GR. Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc Natl Acad Sci USA. 1996; 93, 10657–10661.Google Scholar
38.Shakya, R, Watanabe, T, Costantini, F. The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev Cell. 2005; 8, 65–74.CrossRefGoogle ScholarPubMed
39.Arighi, E, Borrello, MG, Sariola, H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005; 16, 441–467.CrossRefGoogle ScholarPubMed
40.Poteryaev, D, Titievsky, A, Sun, YF, et al. GDNF triggers a novel ret-independent Src kinase family-coupled signaling via a GPI-linked GDNF receptor alpha1. FEBS Lett. 1999; 463, 63–66.CrossRefGoogle Scholar
41.Vieira, P, Thomas-Crusells, J, Vieira, A. Internalization of glial cell-derived neurotrophic factor receptor GFR alpha 1 in the absence of the ret tyrosine kinase coreceptor. Cell Mol Neurobiol. 2003; 23, 43–55.CrossRefGoogle ScholarPubMed
42.Wong, A, Bogni, S, Kotka, P, et al. Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform. Mol Cell Biol. 2005; 25, 9661–9673.Google Scholar
43.Jain, S, Encinas, M, Johnson, EM Jr, Milbrandt, J. Critical and distinct roles for key RET tyrosine docking sites in renal development. Genes Dev. 2006; 20, 321–333.CrossRefGoogle ScholarPubMed
44.Stark, K, Vainio, S, Vassileva, G, McMahon, AP. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994; 372, 679–683.Google Scholar
45.Hoppe, CC, Evans, RG, Bertram, JF, Moritz, KM. Effects of dietary protein restriction on nephron number in the mouse. Am J Physiol Regul Integr Comp Physiol. 2007; 292, R1768–R1774.CrossRefGoogle ScholarPubMed
46.Woods, LL, Weeks, DA, Rasch, R. Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis. Kidney Int. 2004; 65, 1339–1348.Google Scholar
47.Henry, T, Torday, J, Magee, T, et al. Maternal food restriction inhibits nephrogenesis by disrupting mesonephric mesenchyme ureteric bud signaling. Early Hum Dev. 2007; 83, S176.CrossRefGoogle Scholar
48.Desai, M, Gayle, D, Babu, J, Ross, MG. Permanent reduction in heart and kidney organ growth in offspring of undernourished rat dams. Am J Obstet Gynecol. 2005; 193, 1224–1232.CrossRefGoogle ScholarPubMed
49.Merlet-Benichou, C, Gilbert, T, Muffat-Joly, M, Lelievre-Pegorier, M, Leroy, B. Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatr Nephrol. 1994; 8, 175–180.Google Scholar
50.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
51.Omori, S, Hida, M, Ishikura, K, Kuramochi, S, Awazu, M. Expression of mitogen-activated protein kinase family in rat renal development. Kidney Int. 2000; 58, 27–37.CrossRefGoogle ScholarPubMed