Skip to main content

Advertisement

SpringerLink
Log in

Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway Is Involved in Corpus Luteum Regression in Rats

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Endoplasmic reticulum stress (ERS), which is a novel pathway of regulating cellular apoptosis and the function of ERS during corpus luteum (CL) regression, is explored. Early-luteal stage (day 2), mid-luteal stage (day 7), and late-luteal stage (day 14 and 20) were induced, and the apoptosis of luteal cells was detected by a terminal 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL) assay. The apoptotic cells were increased with the regression of CL, especially during the late-luteal stage. The ERS markers glucose-regulated protein 78 (Grp78), CCAAT/enhancer-binding protein homologous protein (CHOP), X-box binding protein 1 (XBP1), activating transcription factor 6α (ATF6α), eukaryotic initiation factor 2α (eIF2α), inositol-requiring protein 1α (IRE1α), caspase 12, and apoptosis marker caspase 3 were analyzed by real-time polymerase chain reaction (PCR) and immunohistochemistry, in agreement with the results of the TUNEL assay; the expression levels of CHOP, caspase 12, and caspase 3 were increased during the process of CL regression. Luteal cells were isolated and cultured in vitro, and the apoptosis of luteal cells was induced by prostaglandin F2α. The ERS was attenuated by the ERS inhibitor tauroursodeoxycholic acid, and the apoptotic rate was analyzed by flow cytometry. The ERS markers Grp78, CHOP, XBP1s, ATF6α, eIF2α, IRE1α, caspase 12, and apoptotic execute marker caspase 3 were analyzed by real-time PCR and immunofluorescence, and the results suggested that the expression of CHOP, caspase 12, and caspase 3 were increased, and there was increased apoptosis of luteal cells. But the expression of IRE1α/XBP1s and eIF2α was not detected. Taken together, the ERS is involved in the CL regression of rats through the CHOP and caspase 12 pathway.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bowen-Shauver JM, Gibori G. The corpus luteum of pregnancy. In: Leung PCK, Adashi EY (eds.), The Ovary. San Diego: Elseiver Inc., Academic Press; 2004:201–230.

    Chapter  Google Scholar 

  2. Stouffer RL. The function and regulation of cell populations comprising the corpus luteum during the ovarian cycle. In: Leung PCK, Adashi EY (eds.), The Ovary. San Diego: Elseiver Inc., Academic Press; 2004:169–184.

    Chapter  Google Scholar 

  3. Choi J, Jo M, Lee E, Choi D. The role of autophagy in corpus luteum regression in the rat. Biol Reprod. 2011;85(3):465–472.

    Article  CAS  PubMed  Google Scholar 

  4. John S Davis, Bo R Rueda. Recent advancements in corpus luteum development, function, maintenance and regression: Forum introduction. Reprod Biol Endocrinol. 2003;1(1):86.

    Article  PubMed Central  Google Scholar 

  5. Stocco C, Telleria C, Gibori G. The molecular control of corpus luteum formation, function, and regression. Endocr Rev. 2007; 28(1):117–149.

    Article  CAS  PubMed  Google Scholar 

  6. Juengel JL, Garverick HA, Johnson AL, Youngquist RS, Smith MF. Apoptosis during luteal regression in cattle. Endocrinology. 1993;132(1):249–254.

    Article  CAS  PubMed  Google Scholar 

  7. Rueda BR, Tilly KI, Botros IW, et al. Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. Biol Reprod. 1997;56(1):186–193.

    Article  CAS  PubMed  Google Scholar 

  8. Bowen JM, Keyes PL, Warren JSm, Townson DH. Prolactin-induced regression of the rat corpus luteum: expression of monocyte chemoattractant protein-1 and invasion of macrophages. Biol Reprod. 1996;54(5): 1120–1127.

    Article  CAS  PubMed  Google Scholar 

  9. Gaytan F, Morales C, Bellido C, et al. Progesterone on an oestrogen background enhances prolactin-induced apoptosis in regressing corpora lutea in the cyclic rat: possible involvement of luteal endothelial cell progesterone receptors. J Endocrinol. 2000;165(3):715–724.

    Article  CAS  PubMed  Google Scholar 

  10. Telleria CM, Goyeneche AA, Cavicchia JC, Stati AO, Deis RP. Apoptosis induced by antigestagen RU486 in rat corpus luteum of pregnancy. Endocrine. 2001;15(2):147–155.

    Article  CAS  PubMed  Google Scholar 

  11. Rueda BR, Wegner JA, Marion SL, Wahlen DD, Hoyer PB. Internucleosomal DNA fragmentation in ovine luteal tissue associated with luteolysis: in vivo and in vitro analyses. Biol Reprod. 1995; 52(2):305–312.

    Article  CAS  PubMed  Google Scholar 

  12. Shikone T, Yamoto M, Kokawa K, Yamashita K, Nishimori K, Nakano R. Apoptosis of human corpora lutea during cyclic luteal regression and early pregnancy. J Clin Endocrinol Metab. 1996; 81(6):2376–2380.

    CAS  PubMed  Google Scholar 

  13. Quirk SM, Harman RM, Huber SC, Cowan RG. Responsiveness of mouse corpora luteal cells to Fas antigen (CD95)-mediated apoptosis. Biol Reprod. 2000;63(1):49–56.

    Article  CAS  PubMed  Google Scholar 

  14. Carambula SF, Pru JK, Lynch MP, et al. Prostaglandin F2alpha-and FAS-activating antibody induced regression of the corpus luteum involves caspase-8 and is defective in caspase-3 deficient mice. Reprod Biol Endocrinol. 2003;1:15.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dauffenbach LM, Khan SM, Yeh J. Corpus luteum regression in the rat in vivo and in vitro studies of apoptotic mechanisms. J Med. 2003;34(1–6):87–100.

    CAS  PubMed  Google Scholar 

  16. Park HJ, Park SJ, Koo DB, et al. Unfolding protein response signaling is involved in development, maintenance, and regression of the corpus luteum during the bovine estrous cycle. Biochem Biophys Res Commun. 2013;441(2):344–350.

    Article  CAS  PubMed  Google Scholar 

  17. Kogure K, Nakamura K, Ikeda S, et al. Glucose-regulated protein, 78-kilodalton is a modulator of luteinizing hormone receptor expression in luteinizing granulosa cells in rats. Biol Reprod. 2013;88(1):8.

    Article  PubMed  CAS  Google Scholar 

  18. Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35(4): 373–381.

    Article  CAS  PubMed  Google Scholar 

  19. Kim R, Emi M, Tanabe K, Murakami S. Role of the unfolded protein response in cell death. Apoptosis. 2006;11(1):5–13.

    Article  CAS  PubMed  Google Scholar 

  20. Rasheva VI, Domingos PM. Cellular responses to endoplasmic reticulum stress and apoptosis. Apoptosis. 2009;14(8): 996–1007.

    Article  PubMed  Google Scholar 

  21. Shore GC, Papa FR, Oakes SA. Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 2011;23(2):143–149.

    Article  CAS  PubMed  Google Scholar 

  22. Tsutsumi S, Gotoh T, Tomisato W, et al. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis. Cell Death Differ. 2004;11(9):1009–1016.

    Article  CAS  PubMed  Google Scholar 

  23. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2008;7(12):1013–1030.

    CAS  PubMed  Google Scholar 

  24. Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998;12(7):982–995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Beuers U.Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(6):318–328.

    Article  CAS  PubMed  Google Scholar 

  26. Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137–1140.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Zhang JY, Diao YF, Kim HR, Jin DI. Inhibition of endoplasmic reticulum stress improves mouse embryo development. PLoS One. 2012;7(7):e40433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang J, Zhu G, Wang X, Xu B, Hu L. Apoptosis and expression of protein TRAIL in granulosa cells of rats with polycystic ovarian syndrome. J Huazhong Univ Sci Technolog Med Sci. 2007; 27(3):311–314.

    Article  CAS  PubMed  Google Scholar 

  29. Kim JS, Song BS, Lee KS, et al. Tauroursodeoxycholic Acid Enhances the Pre-implantation Embryo Development by Reducing Apoptosis in Pigs. Reprod Domest Anim. 2012; 47(5):791–798.

    Article  CAS  PubMed  Google Scholar 

  30. Abraham T, Pin CL, Watson AJ. Embryo collection induces transient activation of XBP1 arm of the ER stress response while embryo vitrification does not. Mol Hum Reprod. 2012;18(5): 229–242.

    Article  CAS  PubMed  Google Scholar 

  31. Hao L, Vassena R, Wu G, et al. The unfolded protein response contributes to preimplantation mouse embryo death in the DDK syndrome. Biol Reprod. 2009;80(5):944–953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lin P, Yang Y, Li X, et al. Endoplasmic reticulum stress is involved in granulosa cell apoptosis during follicular atresia in goat ovaries. Mol Reprod Dev. 2012;79(6):423–432.

    Article  CAS  PubMed  Google Scholar 

  33. Yang Y, Lin P, Chen F, et al. Luman recruiting factor regulates endoplasmic reticulum stress in mouse ovarian granulosa cell apoptosis. Theriogenology. 2013;79(4):633–639.

    Article  CAS  PubMed  Google Scholar 

  34. Simmons D, Kennedy T. Induction of glucose-regulated protein 78 in rat uterine glandular epithelium during uterine sensitization for the decidual cell reaction. Biol Reprod. 2000;62(5):1168–1176.

    Article  CAS  PubMed  Google Scholar 

  35. Liu AX, He WH, Yin LJ, et al. Sustained endoplasmic reticulum stress as a cofactor of oxidative stress in decidual cells from patients with early pregnancy loss. J Clin Endocrinol Metab. 2011;96(3):E493–E497.

    Article  CAS  PubMed  Google Scholar 

  36. Iwawaki T, Akai R, Yamanaka S, et al. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A. 2009;106(39): 16657–16662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lian IA, Løset M, Mundal SB, et al. Increased endoplasmic reticulum stress in decidual tissue from pregnancies complicated by fetal growth restriction with and without pre-eclampsia. Placenta. 2011;32(11):823–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yung HW, Calabrese S, Hynx D, et al. Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol. 2008;173(2):451–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang Z, Wang H, Xu ZM, et al. Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta. Toxicol Appl Pharmacol. 2012;259(2): 236–247.

    Article  CAS  PubMed  Google Scholar 

  40. Burton G, Yung HW, Cindrova-Davies T, Charnock-Jones DS. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2009;30(suppl A):S43–S48.

    Article  PubMed  CAS  Google Scholar 

  41. Løset M, Mundal SB, Johnson MP, et al. A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol. 2011; 204(1):84.e1–e27.

    Article  CAS  Google Scholar 

  42. Kizuka F, Tokuda N, Takagi K, et al. Involvement of bone marrow-derived vascular progenitor cells in neovascularization during formation of the corpus luteum in mice. Biol Reprod. 2012;87(3):55.

    Article  PubMed  CAS  Google Scholar 

  43. Araki E, Oyadomari S, Mori M. Endoplasmic reticulum stress and diabetes mellitus. Intern Med. 2003;42(1):7–14.

    Article  PubMed  Google Scholar 

  44. Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000;403(6765):98–103.

    Article  CAS  PubMed  Google Scholar 

  45. Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J, Fukuuchi Y. Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Neuroscience. 2003;118(2):491–499.

    Article  CAS  PubMed  Google Scholar 

  46. Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K, Tohyama M. Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neurosci Lett. 2004;357(2): 127–130.

    Article  CAS  PubMed  Google Scholar 

  47. Shiraishi H, Okamoto H, Yoshimura A, Yoshida H. ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci. 2006; 119(pt 19):3958–3966.

    Article  CAS  PubMed  Google Scholar 

  48. Sokka AL, Putkonen N, Mudo G, et al. Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain. J Neurosci. 2007;27(4):901–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lu X, Li Y, Wang W, et al. 3ß-Hydroxysteroid-Δ 24 Reductase (DHCR24) Protects Neuronal Cells from Apoptotic Cell Death Induced by Endoplasmic Reticulum (ER) Stress. PLoS One. 2014;9(1):e86753.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993;74(4): 609–619.

    Article  CAS  PubMed  Google Scholar 

  51. Williams GT, Smith CA. Molecular regulation of apoptosis: genetic controls on cell death. Cell. 1993;74(5):777–779.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, 75004, Yinchuan, Ningxia, P.R. China

    Yanzhou Yang PhD, Miao Sun BS, Yuanyuan Shan MS, Xiaomin Zheng PhD, Huiming Ma PhD, Wenzhi Ma PhD, Zhisheng Wang PhD, Xiuying Pei MS & Yanrong Wang MS

Authors
  1. Yanzhou Yang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miao Sun BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuanyuan Shan MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaomin Zheng PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Huiming Ma PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenzhi Ma PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhisheng Wang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiuying Pei MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanrong Wang MS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiuying Pei MS or Yanrong Wang MS.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Sun, M., Shan, Y. et al. Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway Is Involved in Corpus Luteum Regression in Rats. Reprod. Sci. 22, 572–584 (2015). https://doi.org/10.1177/1933719114553445

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719114553445

Keywords

Search

Navigation