Skip to main content

Advertisement

SpringerLink
Log in

Abnormality of Klotho Signaling Is Involved in Polycystic Ovary Syndrome

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

Abstract

This study investigated the involvement of the klotho-associated signaling in the apoptosis of granulosa cells (GCs) from the ovaries of patients with polycystic ovary syndrome (PCOS) and PCOS animals. Primary GCs were obtained from 26 healthy women and 43 women with PCOS. The PCOS animal model was established by the injection of dehydroepiandrosterone (DHEA). Klotho protein and associated microRNA expression in human primary GCs and rats’ ovarian tissues were measured by Western blot and real-time polymerase chain reaction, respectively. Results showed that significantly lower miR-l 26-5p and miR-29a-5p microRNA expressions, higher klotho protein expression, lower insulin growth factor 1 (IGF-lR) and Wnt family member 1 (Wntl) protein expressions, and lower Akt phosphorylation at Ser473 and Thr308 residues were observed in the GCs from patients with PCOS and the ovarian tissues of PCOS rats compared to that in GCs from healthy women and ovarian tissues of normal control rats, respectively. Knockdown of klotho gene expression normalized IGF-lR and Wntl protein expressions and Akt phosphorylation in GCs from patients with PCOS and the ovarian tissues from PCOS rats; it also blocked the effects of insulin on apoptosis and proliferation in GCs from patients with PCOS and inhibited caspase-3 activity in ovarian tissues of PCOS rats. Knockdown of klotho gene expression increased the pregnancy rate in DHEA-treated female rats and increased the body weight of their newborns through normalizing the ovarian function and decreasing the formation of cystic follicles. In conclusion, the miR-l 26-5p, miR-29a-5p/klotho/insulin-IGF-l, Wnt, and Akt signal pathway may be involved in the apoptosis of GCs and subsequent development of PCOS.

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. Li X, Feng Y, Lin JF, Billig H, Shao R. Endometrial progesterone resistance and PCOS. JBiomed Sci. 2014;21(1):2.

    Google Scholar 

  2. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future perspective. Front Biosci (Elite Ed). 2014;6: 104–119.

    Google Scholar 

  3. Meng Y, Qian Y, Gao L, Cai LB, Cui YG, Liu JY. Downregulated expression of peroxiredoxin 4 in granulosa cells from polycystic ovary syndrome. PloS One. 2013;8(10):e76460.

    Google Scholar 

  4. Mikaeili S, Rashidi BH, Safa M, et al. Altered FoxO3 expression and apoptosis in granulosa cells of women with polycystic ovary syndrome. Arch Gynecol Obstet. 2016;294(1):185–192.

    CAS  PubMed  Google Scholar 

  5. Ding L, Gao F, Zhang M, et al. Higher PDCD4 expression is associated with obesity, insulin resistance, lipid metabolism disorders, and granulosa cell apoptosis in polycystic ovary syndrome. Fertil Steril. 2016;105(5):1330–1337.

    CAS  PubMed  Google Scholar 

  6. Wu XQ, Wang YQ, Xu SM, et al. The WNT/p-catenin signaling pathway may be involved in granulosa cell apoptosis from patients with PCOS in North China. J Gynecol Obstet Hum Reprod. 2017;46(1):93–99.

    PubMed  Google Scholar 

  7. Zhao KK, Cui YG, Jiang YQ, et al. Effect of HSP10 on apoptosis induced by testosterone in cultured mouse ovarian granulosa cells. Eur J Obstet Gynecol Reprod Biol. 2013;171(2):301–306.

    CAS  PubMed  Google Scholar 

  8. 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. JHuazhong Univ Sci Technol Med Sci. 2007;27(3):311–314.

    CAS  Google Scholar 

  9. Honnma H, Endo T, Henmi H, et al. Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Apoptosis. 2006;11(9):1525–1533.

    CAS  PubMed  Google Scholar 

  10. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297.

    CAS  Google Scholar 

  11. Hossain MM, Cao M, Wang Q, et al. Altered expression of miR-NAs in a dihydrotestosterone-induced rat PCOS model. J Ovarian Res. 2013;6(1):36.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Scalici E, Traver S, Mullet T, et al. Circulating microRNAs in follicular fluid, powerful tools to explore in vitro fertilization process. Sci Rep. 2016;6:24976.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ding CF, Chen WQ, Zhu YT, Bo YL, Hu HM, Zheng RH. Circulating microRNAs in patients with polycystic ovary syndrome. Hum Fertil (Camb). 2015;18(1):22–29.

    CAS  Google Scholar 

  14. Roth LW, McCallie B, Alvero R, Schoolcraft WB, Minjarez D, Katz-Jaffe MG. Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome. J Assist Reprod Genet. 2014;31(3):355–362.

    PubMed  PubMed Central  Google Scholar 

  15. Sang Q, Yao Z, Wang H, et al. Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J ClinEndocrinol Metab. 2013;98(7):3068–3079.

    CAS  Google Scholar 

  16. Wang Y, Sun Z. Current understanding ofklotho. Ageing Res Rev. 2009;8(1):43–51.

    PubMed  Google Scholar 

  17. Tang X, Wang Y, Fan Z, et al. Klotho: a tumor suppressor and modulator of the Wnt/p-catenin pathway in human hepatocellular carcinoma. Lab Invest. 2016;96(2):197–205.

    CAS  PubMed  Google Scholar 

  18. Xie B, Chen J, Liu B, Zhan J. Klotho acts as a tumor suppressor in cancers. Pathol Oncol Res. 2013;19(4):611–617.

    CAS  PubMed  Google Scholar 

  19. Fu T, Kemper JK. Chapter Seven-MicroRNA-34a and impaired FGF19/21 signaling in obesity. Vitam Horm. 2016;101:175–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Shibayama Y, Kondo T, Ohya H, Fujisawa SI, Teshima T, Iseki K. Upregulation of microRNA-126-5p is associated with drug resistance to cytarabine and poor prognosis in AML patients. Oncol Rep. 2015;33(5):2176–2182.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. He XJ, Ma YY, Yu S, et al. Up-regulated miR-199a-5p in gastric cancer functions as an oncogene and targets klotho. BMC Cancer. 2014;14:218.

    PubMed  PubMed Central  Google Scholar 

  22. Takahashi M, Eda A, Fukushima T, Hohjoh H. Reduction of type IV collagen by upregulated miR-29 in normal elderly mouse and klotho-deficient, senescence-model mouse. PLoS One. 2012;7(11):e48974.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mehi SJ, Maltare A, Abraham CR, King GD. MicroRNA-339 and microRNA-556 regulate klotho expression in vitro. Age. 2014;36(1):141–149.

    CAS  PubMed  Google Scholar 

  24. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41–47.

    Google Scholar 

  25. Iwase A, Ando H, Kuno K, Mizutani S. Use of follicle-stimulating hormone test to predict poor response in in vitro fertilization. Obstet Gynecol. 2005;105(3):645–652.

    CAS  PubMed  Google Scholar 

  26. Goto M, Iwase A, Ando H, Kurotsuchi S, Harata T, Kikkawa F. PTEN and Akt expression during growth of human ovarian follicles. J Assist Reprod Genet. 2007;24(11):541–546.

    PubMed  PubMed Central  Google Scholar 

  27. Yang MY, Rajamahendran R. Morphological and biochemical identification of apoptosis in small, medium, and large bovine follicles and the effects of follicle-stimulating hormone and insulin-like growth factor-i on spontaneous apoptosis in cultured bovine granulosa cells. BiolReprodution. 2000;62(5):1209–1217.

    CAS  Google Scholar 

  28. Zhang Y, Wang Y, Wang L, Bai M, Zhang X, Zhu X. Dopamine receptor D2 and associated microRNAs are involved in stress susceptibility and resistance to escitalopram treatment. Int J Neuropsychopharmacol. 2015;18(8):pyv025.

    PubMed  PubMed Central  Google Scholar 

  29. Wolf I, Levanon-Cohen S, Bose S, et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene. 2008;27(56):7094–7105.

    CAS  PubMed  Google Scholar 

  30. Lin Y, Sun Z. Antiaging gene Klotho enhances glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 in MIN6 b-cells. Endocrinology. 2012;153(7): 3029–3039.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Abramovich D, Irusta G, Bas D, Cataldi NI, Parborell F, Tesone M. Angiopoietins/TIE2 system and VEGF are involved in ovarian function in a DHEA rat model of polycystic ovary syndrome. Endocrinology. 2012;153(7):3446–3456.

    CAS  PubMed  Google Scholar 

  32. Hsu SC, Huang SM, Lin SH, et al. Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway. Biochem J. 2014;464(2):221–229.

    CAS  PubMed  Google Scholar 

  33. Goodarzi MO, Carmina E, Azziz R. DHEA, DHEAS and PCOS. J Steroid Biochem Mol Biol. 2015;145:213–225.

    CAS  PubMed  Google Scholar 

  34. Li XX, Huang LY, Peng JJ, et al. Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. Int J Oncol. 2014;45(2):611–618.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Reproductive Medicine Center, Reproductive Medicine Hospital of Hunan Province, Changsha, Hunan, People’s Republic of China

    Zenghui Mao MD, Qiao Yu MD, Shuwei Luo MD, Xianling Wu MD, Jun Tang MD, Gehua Kang MD & Le Tang MD

  2. Institute of Reproduction and Stem Cell Engineering, Central South University, 84 Xiangya Road, Changsha, Hunan, 4l0078, People’s Republic of China

    Liqing Fan MD

Authors
  1. Zenghui Mao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liqing Fan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiao Yu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuwei Luo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianling Wu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Tang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gehua Kang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Le Tang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Liqing Fan MD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, Z., Fan, L., Yu, Q. et al. Abnormality of Klotho Signaling Is Involved in Polycystic Ovary Syndrome. Reprod. Sci. 25, 372–383 (2018). https://doi.org/10.1177/1933719117715129

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719117715129

Keywords

Search

Navigation