Skip to main content
Log in

Leptin protects placental cells from apoptosis induced by acidic stress

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Development of the human placenta is critical for a successful pregnancy. The placenta allows the exchange of oxygen and carbon dioxide and is crucial to manage acid-base balance within a narrow pH. It is known that low pH levels are a risk of apoptosis in several tissues. However, there has been little discussion about the effect of acidic stress in the placenta. Leptin is produced by the placenta with a trophic autocrine effect. Previous results of our group have demonstrated that leptin prevents apoptosis of trophoblast cells under different stress conditions such as serum deprivation and hyperthermia. The purpose of the present work is to evaluate acidic stress consequences in trophoblast explant survival and to determine leptin action in these conditions. For this objective, term human trophoblast explants were cultured at physiological pH (pH 7.4) and at acidic pH (pH 6.8) in the presence or absence of leptin. Western blot assays were performed to study the abundance of active caspase-3 and the p89 fragment of PARP-1. Pro-apoptotic and pro-survival members of Bcl-2 family, as Bax, t-Bid, and Bcl-2, were studied. Moreover, p53 pathway was also evaluated including Mdm-2, the main p53 regulator. Active caspase-3 and cleaved PARP-1 abundances were increased at low extracellular pH. Moreover, t-Bid levels were also augmented as well as p53 expression and phosphorylation on S46. Leptin treatment prevents the consequences of acidosis, decreasing p53 expression and increasing Mdm-2 expression. In summary, this work demonstrated for first time that low pH induces apoptosis of human trophoblast explants involving apoptotic intrinsic pathway, and leptin impairs this effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Allanson E, Waqar T, White C, Tunçalp Ö, Dickinson J (2016) Umbilical lactate as a measure of acidosis and predictor of neonatal risk: a systematic review. BJOG Int J Obstet Gynaecol 124(4):584–594

  • Aoyama K, Burns DM, Suh SW, Garnier P, Matsumori Y, Shiina H, Swanson RA (2005) Acidosis causes endoplasmic reticulum stress and caspase-12-mediated astrocyte death. J Cereb Blood Flow Metab 25(3):358–370

    Article  PubMed  CAS  Google Scholar 

  • Apostolova N, Blas-Garcia A, Esplugues JV (2011) Mitochondria sentencing about cellular life and death: a matter of oxidative stress. Curr Pharm Des 17(36):4047–4060

    Article  PubMed  CAS  Google Scholar 

  • Avagliano L, Locatelli A, Danti L, Felis S, Mecacci F, Bulfamante GP (2015) Placental histology in clinically unexpected severe fetal acidemia at term. Early Hum Dev 91(5):339–343

    Article  PubMed  Google Scholar 

  • Barrientos G, Toro A, Moschansky P, Cohen M, Garcia MG, Rose M, Maskin B, Sanchez-Margalet V, Blois SM, Varone CL (2015) Leptin promotes HLA-G expression on placental trophoblasts via the MEK/Erk and PI3K signaling pathways. Placenta

  • Basanez G, Soane L, Hardwick JM (2012) A new view of the lethal apoptotic pore. PLoS Biol 10(9):e1001399

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bobrow CS, Soothill PW (1999) Causes and consequences of fetal acidosis. Arch Dis Child Fetal Neonatal Ed 80(3):F246–F249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brady CA, Attardi LD (2010) p53 at a glance. J Cell Sci 123(15):2527–2532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brenner D, Mak TW (2009) Mitochondrial cell death effectors. Curr Opin Cell Biol 21(6):871–877

    Article  PubMed  CAS  Google Scholar 

  • Cartwright JE, Keogh RJ, van Patot MCT (2007) Hypoxia and placental remodelling. Hypoxia and the Circulation. Springer, Berlin, pp 113–126

    Book  Google Scholar 

  • Cartwright JE, Fraser R, Leslie K, Wallace AE, James JL (2010) Remodelling at the maternal–fetal interface: relevance to human pregnancy disorders. Reproduction 140(6):803–813

    Article  PubMed  CAS  Google Scholar 

  • Castro-Parodi M, Szpilbarg N, Dietrich V, Sordelli M, Reca A, Abán C, Maskin B, Farina M, Damiano AE (2013) Oxygen tension modulates AQP9 expression in human placenta. Placenta 34(8):690–698

    Article  PubMed  CAS  Google Scholar 

  • Chaitanya GV, Alexander JS, Babu PP (2010) PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun Signal 8(1):31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cohen M, Meisser A, Haenggeli L, Irminger-Finger I, Bischof P (2007) Status of p53 in first-trimester cytotrophoblastic cells. Mol Hum Reprod 13(2):111–116

    Article  PubMed  CAS  Google Scholar 

  • Dai C, Gu W (2010) p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med 16(11):528–536

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Desoye G, Hauguel-de Mouzon S (2007) The human placenta in gestational diabetes mellitus. Diabetes Care 30(Supplement 2):S120–S126

    Article  PubMed  CAS  Google Scholar 

  • Dong B, Zhou H, Han C, Yao J, Xu L, Zhang M, Fu Y, Xia Q (2014) Ischemia/reperfusion-induced CHOP expression promotes apoptosis and impairs renal function recovery: the role of acidosis and GPR4. PLoS One 9(10):e110944

    Article  PubMed  PubMed Central  Google Scholar 

  • Eischen CM, Lozano G (2014) The Mdm network and its regulation of p53 activities: a rheostat of cancer risk. Hum Mutat 35(6):728–737

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eskes R, Desagher S, Antonsson B, Martinou J-C (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20(3):929–935

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eskild A, Strøm-Roum EM, Haavaldsen C (2016) Does the biological response to fetal hypoxia involve angiogenesis, placental enlargement and preeclampsia? Paediatr Perinat Epidemiol 30(3):305–309

    Article  PubMed  PubMed Central  Google Scholar 

  • Frühbeck G, Jebb S, Prentice A (1998) Leptin: physiology and pathophysiology. Clin Physiol 18(5):399–419

    Article  PubMed  Google Scholar 

  • Gottlieb TM, Leal JFM, Seger R, Taya Y, Oren M (2002) Cross-talk between Akt, p 53 and Mdm 2: possible implications for the regulation of apoptosis. Oncogene 21(8):1299–1303

    Article  PubMed  CAS  Google Scholar 

  • Grosfeld A, Turban S, André J, Cauzac M, Challier J-C, Hauguel-de Mouzon S, Guerre-Millo M (2001) Transcriptional effect of hypoxia on placental leptin. FEBS Lett 502(3):122–126

    Article  PubMed  CAS  Google Scholar 

  • Harmon AC, Cornelius DC, Amaral LM, Faulkner JL, Cunningham MW, Wallace K, LaMarca B (2016) The role of inflammation in the pathology of preeclampsia. Clin Sci 130(6):409–419

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heazell AE, Sharp AN, Baker PN, Crocker IP (2011) Intra-uterine growth restriction is associated with increased apoptosis and altered expression of proteins in the p53 pathway in villous trophoblast. Apoptosis 16(2):135–144

    Article  PubMed  CAS  Google Scholar 

  • Herrid M, Palanisamy S, Ciller UA, Fan R, Moens P, Smart NA, McFarlane JR (2014) An updated view of leptin on implantation and pregnancy: a review. Physiol Res 63:543–557

    PubMed  CAS  Google Scholar 

  • Houseknecht KL, Baile CA, Matteri RL, Spurlock ME (1998) The biology of leptin: a review. J Anim Sci 76(5):1405–1420

    Article  PubMed  CAS  Google Scholar 

  • Huppertz B, Herrler A (2005) Regulation of proliferation and apoptosis during development of the preimplantation embryo and the placenta. Birth Defects Res C Embryo Today 75(4):249–261

    Article  PubMed  CAS  Google Scholar 

  • Huppertz B, Kadyrov M, Kingdom JC (2006) Apoptosis and its role in the trophoblast. Am J Obstet Gynecol 195(1):29–39

    Article  PubMed  Google Scholar 

  • Inoue T, Wu L, Stuart J, Maki CG (2005) Control of p53 nuclear accumulation in stressed cells. FEBS Lett 579(22):4978–4984

    Article  PubMed  CAS  Google Scholar 

  • James JL, Stone P, Chamley L (2006) The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model. Hum Reprod 21(10):2699–2705

    Article  PubMed  Google Scholar 

  • Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ 19(1):42–50

    Article  PubMed  CAS  Google Scholar 

  • Khacho M, Tarabay M, Patten D, Khacho P, MacLaurin JG, Guadagno J, Bergeron R, Cregan SP, Harper M-E, Park DS (2014) Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival. Nat Commun 5:ncomms4550

    Article  Google Scholar 

  • Kim JY, Cheng X, Wölfl S (2017) Acidic stress induced G1 cell cycle arrest and intrinsic apoptotic pathway in Jurkat T-lymphocytes. Exp Cell Res 350(1):140–146

    Article  PubMed  CAS  Google Scholar 

  • Knöfler M, Pollheimer J (2013) Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling. Front Genet 4:190

    Article  PubMed  PubMed Central  Google Scholar 

  • Levy R, Nelson DM (2000) To be, or not to be, that is the question. Apoptosis in human trophoblast. Placenta 21(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Lin Y-R, Li C-J, Syu S-H, Wen C-H, Buddhakosai W, Wu H-P, Hsu Chen C, Lu H-E, Chen W-L (2016) Early administration of glutamine protects cardiomyocytes from post-cardiac arrest acidosis. Biomed Res Int 2016:2106342

    PubMed  PubMed Central  Google Scholar 

  • Magarinos MP, Sanchez-Margalet V, Kotler M, Calvo JC, Varone CL (2007) Leptin promotes cell proliferation and survival of trophoblastic cells. Biol Reprod 76(2):203–210

    Article  PubMed  CAS  Google Scholar 

  • Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3(9):1029–1033

    Article  PubMed  CAS  Google Scholar 

  • Meek DW, Anderson CW (2009) Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol 1(6):a000950

    Article  PubMed  PubMed Central  Google Scholar 

  • Meißner U, Spranger R, Lehner M, Allabauer I, Rascher W, Dötsch J (2005) Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis. Eur J Endocrinol 153(3):455–461

    Article  PubMed  Google Scholar 

  • Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, Mori T, Masuzaki H, Hosoda K, Ogawa Y (1998) Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia 1. J Clin Endocrinol Metab 83(9):3225–3229

    PubMed  CAS  Google Scholar 

  • Omo-Aghoja L (2014) Maternal and fetal acid-base chemistry: a major determinant of perinatal outcome. Ann Med \Health Sci Res 4(1):8–17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ortner CM, Combrinck B, Allie S, Story D, Landau R, Cain K, Dyer R (2015) Strong ion and weak acid analysis in severe preeclampsia: potential clinical significance. Br J Anaesth 115(2):275–284

    Article  PubMed  CAS  Google Scholar 

  • Perez-Perez A, Maymo J, Duenas JL, Goberna R, Calvo JC, Varone C, Sanchez-Margalet V (2008) Leptin prevents apoptosis of trophoblastic cells by activation of MAPK pathway. Arch Biochem Biophys 477(2):390–395

    Article  PubMed  CAS  Google Scholar 

  • Perez-Perez A, Maymo J, Gambino Y, Duenas JL, Goberna R, Varone C, Sanchez-Margalet V (2009) Leptin stimulates protein synthesis-activating translation machinery in human trophoblastic cells. Biol Reprod 81(5):826–832

    Article  PubMed  CAS  Google Scholar 

  • Perez-Perez A, Gambino Y, Maymo J, Goberna R, Fabiani F, Varone C, Sanchez-Margalet V (2010) MAPK and PI3K activities are required for leptin stimulation of protein synthesis in human trophoblastic cells. Biochem Biophys Res Commun 396(4):956–960

    Article  PubMed  CAS  Google Scholar 

  • Perez-Perez A, Sanchez-Jimenez F, Maymo J, Duenas JL, Varone C, Sanchez-Margalet V (2015) Role of leptin in female reproduction. Clin Chem Lab Med 53(1):15–28

    Article  PubMed  CAS  Google Scholar 

  • Pérez-Pérez A, Toro AR, Vilarino-Garcia T, Guadix P, Maymó JL, Dueñas JL, Varone CL, Sánchez-Margalet V (2016) Leptin reduces apoptosis triggered by high temperature in human placental villous explants: the role of the p53 pathway. Placenta 42:106–113

    Article  PubMed  Google Scholar 

  • Pérez-Pérez A, Vilariño-García T, Fernández-Riejos P, Martín-González J, Segura-Egea JJ, Sánchez-Margalet V (2017a) Role of leptin as a link between metabolism and the immune system. Cytokine Growth Factor Rev 35:71–84

    Article  PubMed  Google Scholar 

  • Pérez-Pérez A, Toro A, Vilariño-García T, Maymó J, Guadix P, Dueñas JL, Fernández-Sánchez M, Varone C, Sánchez-Margalet V (2017b) Leptin action in normal and pathological pregnancies. J Cell Mol Med 22(2):716–727

  • Pringle K, Kind K, Sferruzzi-Perri A, Thompson J, Roberts C (2009) Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy. Hum Reprod Update:dmp046

  • Rehman K, Akash MSH, Alina Z (2018) Leptin: a new therapeutic target for treatment of diabetes mellitus. J Cell Biochem 119(7):5016–5027

    Article  PubMed  CAS  Google Scholar 

  • Rodesch F, Simon P, Donner C, Jauniaux E (1992) Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 80(2):283–285

    PubMed  CAS  Google Scholar 

  • Schanton M, Maymó JL, Pérez-Pérez A, Sanchez-Margalet V, Varone C (2017) Involvement of leptin in the molecular physiology of the placenta. Reproduction 155(1):R1–R12

  • Sharma V, Kaur R, Bhatnagar A, Kaur J (2015) Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling. Cell Stress Chaperones 20(3):431–440

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sharp AN, Heazell AE, Crocker IP, Mor G (2010) Placental apoptosis in health and disease. Am J Reprod Immunol 64(3):159–169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87(7):1157–1180

    Article  PubMed  CAS  Google Scholar 

  • Sohr S, Engeland K (2011) The tumor suppressor p53 induces expression of the pregnancy-supporting human chorionic gonadotropin (hCG) CGB7 gene. Cell Cycle 10(21):3758–3767

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Toro AR, Maymó JL, Ibarbalz FM, Pérez AP, Maskin B, Faletti AG, Margalet VS, Varone CL (2014) Leptin is an anti-apoptotic effector in placental cells involving p53 downregulation. PLoS One 9(6):e99187

    Article  PubMed  PubMed Central  Google Scholar 

  • Toro AR, Pérez-Pérez A, Gutiérrez IC, Sánchez-Margalet V, Varone CL (2015) Mechanisms involved in p53 downregulation by leptin in trophoblastic cells. Placenta 36(11):1266–1275

    Article  PubMed  CAS  Google Scholar 

  • Tzschoppe A, Struwe E, Rascher W, Dörr HG, Schild RL, Goecke TW, Beckmann MW, Hofner B, Kratzsch J, Dötsch J (2011) Intrauterine growth restriction (IUGR) is associated with increased leptin synthesis and binding capability in neonates. Clin Endocrinol 74(4):459–466

    Article  CAS  Google Scholar 

  • Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49(23):6449–6465

    PubMed  CAS  Google Scholar 

  • Wulff C, Weigand M, Kreienberg R, Fraser HM (2003) Angiogenesis during primate placentation in health and disease. Reproduction 126(5):569–577

    Article  PubMed  CAS  Google Scholar 

  • Yang JM, Wang KG (1995) Relationship between acute fetal distress and maternal-placental-fetal circulations in severe preeclampsia. Acta Obstet Gynecol Scand 74(6):419–424

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This work was supported by a grant from the Instituto de Salud Carlos III (PS09/00119 and PI12/01172), funded in part by FEDER Funds, and ART is supported by a CONICET fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Víctor Sánchez-Margalet.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Antonio Pérez-Pérez and Ayelén Toro contribute equally to this work as first authors

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pérez-Pérez, A., Toro, A., Vilariño-Garcia, T. et al. Leptin protects placental cells from apoptosis induced by acidic stress. Cell Tissue Res 375, 733–742 (2019). https://doi.org/10.1007/s00441-018-2940-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-018-2940-9

Keywords

Navigation