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The expression of Akt and ERK1/2 proteins decreased in dexamethasone-induced intrauterine growth restricted rat placental development

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Abstract

The placenta is a complicated tissue that lies between maternal and fetal compartments. Although the architecture of the human and rodent placentas differ a little in their details, their overall structures and the molecular mechanisms of placental developments are thought to be very similar. In rats, fetal–placental exposure to maternally administered glucocorticoids decreases birth weight and placental weight. The mechanism underlying the placental growth inhibitory effects of glucocorticoids have not been elucidated. Moreover it is still not determined that how Akt and ERK1/2 proteins related proliferation and apoptosis mechanisms are influenced by dexamethasone-induced IUGR (Intrauterine Growth Restriction) placentas. The aim of this study was to investigate the expression levels and spatio-temporal immunolocalizations of Akt, p-Akt, ERK1/2 and p-ERK1/2 proteins in normal and dexamethasone treated placental development in pregnant Wistar rats. Pregnant rats were subcutaneously injected with 100 μg/kg dexamethasone 21-acetate in 0.1 ml 10% ethanol on day 10 and 12 of gestation. Afterwards injection was continued as 200 μg/kg until they were killed on day 12 (injection started on day 10), 14, 16, 18 and 20 (injections started on day 12) of pregnancy. Placental and embryonal tissues were collected for immunohistochemistry and Western blot analysis. We found that maternal dexamethasone treatment led to a decrease in ERK1/2 and Akt activation during rat placental development. The decrease in Akt and ERK1/2 activations may result with cell survival inhibition or apoptosis stimulation. Hence, dexamethasone induced placental and embryonal developmental abnormalities could be associated with reduction of Akt and ERK1/2 activation.

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References

  • Ain R, Canham LN, Soares MJ (2005) Dexamethasone-induced intrauterine growth restriction impacts the placental prolactin family, insulin-like growth factor-II and the Akt signaling pathway. J Endocrinol 185(2):253–263

    Article  PubMed  CAS  Google Scholar 

  • Baisden B, Sonne S, Joshi RM, Ganapathy V, Shekhawat PS (2007) Antenatal dexamethasone treatment leads to changes in gene expression in a murine late placenta. Placenta 28(10):1082–1090

    Article  PubMed  CAS  Google Scholar 

  • Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS (1993) Fetal nutrition and cardiovascular disease in adult life. Lancet 341(8850):938–941

    Article  PubMed  CAS  Google Scholar 

  • Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR (1993) Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 341(8841):339–341

    Article  PubMed  CAS  Google Scholar 

  • Binetruy B, Heasley L, Bost F, Caron L, Aouadi M (2007) Concise review: regulation of embryonic stem cell lineage commitment by mitogen-activated protein kinases. Stem Cells 25(5):1090–1095

    Article  PubMed  CAS  Google Scholar 

  • Bissonauth V, Roy S, Gravel M, Guillemette S, Charron J (2006) Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis. Development 133(17):3429–3440

    Article  PubMed  CAS  Google Scholar 

  • Blair E, Stanley F (1990) Intrauterine growth and spastic cerebral palsy. I. Association with birth weight for gestational age. Am J Obstet Gynecol 162(1):229–237

    PubMed  CAS  Google Scholar 

  • Bloom SL, Sheffield JS, McIntire DD, Leveno KJ (2001) Antenatal dexamethasone and decreased birth weight. Obstet Gynecol 97(4):485–490

    Article  PubMed  CAS  Google Scholar 

  • Braun T, Li S, Moss TJ, Newnham JP, Challis JR, Gluckman PD, Sloboda DM (2007) Maternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep. J Endocrinol 194(2):337–347

    Article  PubMed  CAS  Google Scholar 

  • Brodsky D, Christou H (2004) Current concepts in intrauterine growth restriction. J Intensive Care Med 19(6):307–319

    Article  PubMed  Google Scholar 

  • Daoud G, Amyot M, Rassart E, Masse A, Simoneau L, Lafond J (2005) ERK1/2 and p38 regulate trophoblasts differentiation in human term placenta. J Physiol 566(Pt 2):409–423

    Article  PubMed  CAS  Google Scholar 

  • Dickinson RJ, Keyse SM (2006) Diverse physiological functions for dual-specificity MAP kinase phosphatases. J Cell Sci 119(Pt 22):4607–4615

    Article  PubMed  CAS  Google Scholar 

  • Forbes K, Westwood M (2008) The IGF axis and placental function a mini review. Horm Res 69(3):129–137

    Article  PubMed  CAS  Google Scholar 

  • Franke TF, Kaplan DR, Cantley LC (1997) PI3 K: downstream AKTion blocks apoptosis. Cell 88(4):435–437

    Article  PubMed  CAS  Google Scholar 

  • Garcia Z, Kumar A, Marques M, Cortes I, Carrera AC (2006) Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J 25(4):655–661

    Article  PubMed  CAS  Google Scholar 

  • Georgiades P, Ferguson-Smith AC, Burton GJ (2002) Comparative developmental anatomy of the murine and human definitive placentae. Placenta 23(1):3–19

    Article  PubMed  CAS  Google Scholar 

  • Giroux S, Tremblay M, Bernard D, Cardin-Girard JF, Aubry S, Larouche L, Rousseau S, Huot J, Landry J, Jeannotte L, Charron J (1999) Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr Biol 9(7):369–372

    Article  PubMed  CAS  Google Scholar 

  • Gluckman PD (2001) Editorial: nutrition, glucocorticoids, birth size, and adult disease. Endocrinology 142(5):1689–1691

    Article  PubMed  CAS  Google Scholar 

  • Hahn D, Blaschitz A, Korgun ET, Lang I, Desoye G, Skofitsch G, Dohr G (2001) From maternal glucose to fetal glycogen: expression of key regulators in the human placenta. Mol Hum Reprod 7(12):1173–1178

    Article  PubMed  CAS  Google Scholar 

  • Hajduch E, Litherland GJ, Hundal HS (2001) Protein kinase B (PKB/Akt)–a key regulator of glucose transport? FEBS Lett 492(3):199–203

    Article  PubMed  CAS  Google Scholar 

  • Hales CN, Desai M, Ozanne SE, Crowther NJ (1996) Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis. Biochem Soc Trans 24(2):341–350

    PubMed  CAS  Google Scholar 

  • Hatano N, Mori Y, Oh-hora M, Kosugi A, Fujikawa T, Nakai N, Niwa H, Miyazaki J, Hamaoka T, Ogata M (2003) Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells 8(11):847–856

    Article  PubMed  CAS  Google Scholar 

  • Hewitt DP, Mark PJ, Waddell BJ (2006) Glucocorticoids prevent the normal increase in placental vascular endothelial growth factor expression and placental vascularity during late pregnancy in the rat. Endocrinology 147(12):5568–5574

    Article  PubMed  CAS  Google Scholar 

  • Jiang BH, Liu LZ (2008) PI3 K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta 1784(1):150–158

    PubMed  CAS  Google Scholar 

  • Johnstone ED, Mackova M, Das S, Payne SG, Lowen B, Sibley CP, Chan G, Guilbert LJ (2005) Multiple anti-apoptotic pathways stimulated by EGF in cytotrophoblasts. Placenta 26(7):548–555

    Article  PubMed  CAS  Google Scholar 

  • Kim D, Chung J (2002) Akt: versatile mediator of cell survival and beyond. J Biochem Mol Biol 35(1):106–115

    Article  PubMed  CAS  Google Scholar 

  • Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351(Pt 2):289–305

    Article  PubMed  CAS  Google Scholar 

  • Korgun ET, Dohr G, Desoye G, Demir R, Kayisli UA, Hahn T (2003) Expression of insulin, insulin-like growth factor I and glucocorticoid receptor in rat uterus and embryo during decidualization, implantation and organogenesis. Reproduction 125(1):75–84

    Article  PubMed  CAS  Google Scholar 

  • Laviola L, Perrini S, Belsanti G, Natalicchio A, Montrone C, Leonardini A, Vimercati A, Scioscia M, Selvaggi L, Giorgino R, Greco P, Giorgino F (2005) Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling. Endocrinology 146(3):1498–1505

    Article  PubMed  CAS  Google Scholar 

  • Levitt NS, Lindsay RS, Holmes MC, Seckl JR (1996) Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology 64(6):412–418

    Article  PubMed  CAS  Google Scholar 

  • Liang J, Slingerland JM (2003) Multiple roles of the PI3 K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2(4):339–345

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    PubMed  CAS  Google Scholar 

  • Luttrell LM (2003) ‘Location, location, location’: activation and targeting of MAP kinases by G protein-coupled receptors. J Mol Endocrinol 30(2):117–126

    Article  PubMed  CAS  Google Scholar 

  • Martins JP, Monteiro JC, Paixao AD (2003) Renal function in adult rats subjected to prenatal dexamethasone. Clin Exp Pharmacol Physiol 30(1–2):32–37

    Article  PubMed  CAS  Google Scholar 

  • McDonald TJ, Franko KL, Brown JM, Jenkins SL, Nathanielsz PW, Nijland MJ (2003) Betamethasone in the last week of pregnancy causes fetal growth retardation but not adult hypertension in rats. J Soc Gynecol Investig 10(8):469–473

    Article  PubMed  CAS  Google Scholar 

  • Meloche S, Vella FD, Voisin L, Ang SL, Saba-El-Leil M (2004) Erk2 signaling and early embryo stem cell self-renewal. Cell Cycle 3(3):241–243

    Article  PubMed  CAS  Google Scholar 

  • Mikula M, Schreiber M, Husak Z, Kucerova L, Ruth J, Wieser R, Zatloukal K, Beug H, Wagner EF, Baccarini M (2001) Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J 20(8):1952–1962

    Article  PubMed  CAS  Google Scholar 

  • Mitsiades CS, Mitsiades N, Koutsilieris M (2004) The Akt pathway: molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 4(3):235–256

    Article  PubMed  CAS  Google Scholar 

  • Nadeau V, Guillemette S, Belanger LF, Jacob O, Roy S, Charron J (2009) Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation. Development 136(8):1363–1374

    Article  PubMed  CAS  Google Scholar 

  • Navarrete Santos A, Tonack S, Kirstein M, Pantaleon M, Kaye P, Fischer B (2004) Insulin acts via mitogen-activated protein kinase phosphorylation in rabbit blastocysts. Reproduction 128(5):517–526

    Article  PubMed  Google Scholar 

  • Neri LM, Borgatti P, Capitani S, Martelli AM (2002) The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system. Biochim Biophys Acta 1584(2–3):73–80

    PubMed  CAS  Google Scholar 

  • Pawson T (2002) Regulation and targets of receptor tyrosine kinases. Eur J Cancer 38(Suppl 5):S3–10

    Article  PubMed  Google Scholar 

  • Pollheimer J, Knofler M (2005) Signalling pathways regulating the invasive differentiation of human trophoblasts: a review. Placenta 26(Suppl 1):S21–30

    Article  PubMed  Google Scholar 

  • Prast J, Saleh L, Husslein H, Sonderegger S, Helmer H, Knofler M (2008) Human chorionic gonadotropin stimulates trophoblast invasion through extracellularly regulated kinase and AKT signaling. Endocrinology 149(3):979–987

    Article  PubMed  CAS  Google Scholar 

  • Qian X, Esteban L, Vass WC, Upadhyaya C, Papageorge AG, Yienger K, Ward JM, Lowy DR, Santos E (2000) The Sos1 and Sos2 Ras-specific exchange factors: differences in placental expression and signaling properties. EMBO J 19(4):642–654

    Article  PubMed  CAS  Google Scholar 

  • Riley JK, Carayannopoulos MO, Wyman AH, Chi M, Ratajczak CK, Moley KH (2005) The PI3 K/Akt pathway is present and functional in the preimplantation mouse embryo. Dev Biol 284(2):377–386

    Article  PubMed  CAS  Google Scholar 

  • Romeis B (1989) Mikroskopische Technik, 17th edn. Urban and Schwarzenberg, Munich

    Google Scholar 

  • Rossant J, Cross JC (2001) Placental development: lessons from mouse mutants. Nat Rev Genet 2(7):538–548

    Article  PubMed  CAS  Google Scholar 

  • Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, Labrecque N, Ang SL, Meloche S (2003) An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 4(10):964–968

    Article  PubMed  CAS  Google Scholar 

  • Seckl JR (1994) Glucocorticoids and small babies. Q J Med 87(5):259–262

    PubMed  CAS  Google Scholar 

  • Sugden MC, Langdown ML, Munns MJ, Holness MJ (2001) Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno-fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growth-retarded adult offspring. Eur J Endocrinol 145(4):529–539

    Article  PubMed  CAS  Google Scholar 

  • Unek G, Ozmen A, Kipmen-Korgun D, Korgun ET (2011) Immunolocalization of PCNA, Ki67, p27 and p57 in normal and dexamethasone-induced intrauterine growth restriction placental development in rat. Acta Histochem. doi:10.1016/j.acthis.2011.02.002

  • Waddell BJ, Hisheh S, Dharmarajan AM, Burton PJ (2000) Apoptosis in rat placenta is zone-dependent and stimulated by glucocorticoids. Biol Reprod 63(6):1913–1917

    Article  PubMed  CAS  Google Scholar 

  • Watson ED, Cross JC (2005) Development of structures and transport functions in the mouse placenta. Physiology (Bethesda) 20:180–193

    CAS  Google Scholar 

  • Yang ZZ, Tschopp O, Hemmings-Mieszczak M, Feng J, Brodbeck D, Perentes E, Hemmings BA (2003) Protein kinase B alpha/Akt1 regulates placental development and fetal growth. J Biol Chem 278(34):32124–32131

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Research Foundation of Akdeniz University, Antalya, Turkey (project number: 2007.02.0122.013).

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Authors and Affiliations

  1. Department of Histology and Embryology, Medical Faculty, Akdeniz University, 07070, Antalya, Turkey

    Asli Ozmen, Gozde Unek & Emin Turkay Korgun

  2. Department of Biochemistry, Medical Faculty, Akdeniz University, 07070, Antalya, Turkey

    Dijle Kipmen-Korgun

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  1. Asli Ozmen
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  2. Gozde Unek
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Correspondence to Emin Turkay Korgun.

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Ozmen, A., Unek, G., Kipmen-Korgun, D. et al. The expression of Akt and ERK1/2 proteins decreased in dexamethasone-induced intrauterine growth restricted rat placental development. J Mol Hist 42, 237–249 (2011). https://doi.org/10.1007/s10735-011-9328-4

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  • DOI: https://doi.org/10.1007/s10735-011-9328-4

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