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The Emerging Key Role of Klotho in the Hypothalamus–Pituitary–Ovarian Axis

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Abstract

The hypothalamus–pituitary–ovary axis is the most important system for regulating female reproductive endocrine function. Its dysfunction would lead to the abnormal secretion of gonadotropin-releasing hormone, follicle-stimulating hormone, or luteinizing hormone, and eventually result in the occurrence of reproductive disease, such as congenital hypogonadotropic hypogonadism, polycystic ovary syndrome, and premature ovarian failure. Recently, an anti-aging gene, Klotho, has gained broad attention in female reproductive diseases. Reports have shown that Klotho is closely correlated to the hypothalamus–pituitary–ovary axis and plays a key role in the development and progression of reproductive diseases. With this issue, we generally review the physiological and pathological role of Klotho in the hypothalamus–pituitary–ovary axis. We also review the underlying mechanisms of Klotho in promoting and preventing female reproductive diseases, which involve the dysfunction of the fibroblast growth factor–Klotho endocrine system, the abnormal signaling regulation of Wnt-β-catenin and insulin-like growth factor-1, the accumulation of oxidative stress, and the inhibition of autophagy, eventually affecting the genesis, development, ovulation, or atresia of follicles. The present review would provide new insights and potential therapeutic target strategies for clinical strategies.

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References

  1. Stamatiades GA, Carroll RS, Kaiser UB. GnRH-A key regulator of FSH. Endocrinology. 2019;160:57–67.

    CAS  PubMed  Google Scholar 

  2. Wang Y, Sun Z. Current understanding of klotho. Ageing Res Rev. 2009;8:43–51.

    PubMed  Google Scholar 

  3. Kim J, Hwang K, Park K, Kong ID, Cha S. Biological role of anti-aging protein Klotho. J Lifestyle Med. 2015;5:1–6.

    PubMed  PubMed Central  Google Scholar 

  4. Xie B, Chen J, Liu B, Zhan J. Klotho acts as a tumor suppressor in cancers. Pathol Oncol Res. 2013;19:611–7.

    CAS  PubMed  Google Scholar 

  5. Tang X, Wang Y, Fan Z, Ji G, Wang M, Lin J, et al. Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Lab Investig. 2016;96:197–205.

    CAS  PubMed  Google Scholar 

  6. Dalton GD, Xie J, An SW, Huang CL. New insights into the mechanism of action of soluble Klotho. Front Endocrinol. 2017;8:323.

    Google Scholar 

  7. Qi-Feng L, Jian-Ming Y, Zhi-Yong D, Li-Xia Y, Qiang S, Sha-Sha L. Ameliorating effect of Klotho on endoplasmic reticulum stress and renal fibrosis induced by unilateral ureteral obstruction. Iran J Kidney Dis. 2015;9:291–7.

    Google Scholar 

  8. Banerjee S, Zhao Y, Sarkar PS, Rosenblatt KP, Tilton RG, Choudhary S. Klotho ameliorates chemically induced endoplasmic reticulum (ER) stress signaling. Cell Physiol Biochem. 2013;31:659–72.

    CAS  PubMed  Google Scholar 

  9. Yao Y, Wang Y, Zhang Y, Liu C. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways. Lipids Health Dis. 2017;16:77.

    PubMed  PubMed Central  Google Scholar 

  10. Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, et al. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem. 2005;280:38029–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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:e76460.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bookout AL, de Groot MHM, Owen BM, Lee S, Gautron L, Lawrence HL, et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med. 2013;19:1147–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Li S, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K. Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct. 2004;29:91–9.

    CAS  PubMed  Google Scholar 

  14. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.

    CAS  PubMed  Google Scholar 

  15. Yatsenko SA, Rajkovic A. Genetics of human female infertility. Biol Reprod. 2019;101:549–66.

    PubMed  Google Scholar 

  16. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242:626–30.

    CAS  PubMed  Google Scholar 

  17. Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H, et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 1998;424:6–10.

    CAS  PubMed  Google Scholar 

  18. Kuro-O M. The Klotho proteins in health and disease. Nat Rev Nephrol. 2019;15:27–44.

    CAS  PubMed  Google Scholar 

  19. Tohyama O, Imura A, Iwano A, Freund JL, Henrissat B, Fujimori T, et al. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem. 2004;279:9777–84.

    CAS  PubMed  Google Scholar 

  20. Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro-O M, Huang CL. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A. 2008;105:9805–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zeng Y, Wang P, Zhang M, Du J. Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice. Aging Clin Exp Res. 2016;28:69–76.

    PubMed  Google Scholar 

  22. Hum JM, O'Bryan L, Smith RC, White KE. Novel functions of circulating Klotho. Bone. 2017;100:36–40.

    CAS  PubMed  Google Scholar 

  23. Wang Q, Ren D, Li Y, Xu G. Klotho attenuates diabetic nephropathy in db/db mice and ameliorates high glucose-induced injury of human renal glomerular endothelial cells. Cell Cycle. 2019;18:696–707.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Li S, Yu L, He A, Liu Q. Klotho inhibits unilateral ureteral obstruction-induced endothelial-to-mesenchymal transition via TGF-β1/Smad2/Snail1 signaling in mice. Front Pharmacol. 2019;10:348.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ko J, Shin N, Jung T, Shin I, Moon C, Kim S, et al. Melatonin attenuates cisplatin-induced acute kidney injury in rats via induction of anti-aging protein, Klotho. Food Chem Toxicol. 2019;129:201–10.

    CAS  PubMed  Google Scholar 

  26. Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E. Klotho is a neuroprotective and cognition-enhancing protein. Vitam Horm. 2016;101:215–38.

    CAS  PubMed  Google Scholar 

  27. Massó A, Sánchez A, Gimenez-Llort L, Lizcano JM, Cañete M, García B, et al. Secreted and transmembrane αKlotho isoforms have different spatio-temporal profiles in the brain during aging and Alzheimer’s disease progression. PLoS One. 2015;10:e143623.

    Google Scholar 

  28. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, et al. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat. 2012;133:649–57.

    CAS  PubMed  Google Scholar 

  29. Adhikari BR, Uehara O, Matsuoka H, Takai R, Harada F, Utsunomiya M, et al. Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas. Med Mol Morphol. 2017;50:155–60.

    CAS  PubMed  Google Scholar 

  30. Dai D, Wang Q, Li X, Liu J, Ma X, Xu W. Klotho inhibits human follicular thyroid cancer cell growth and promotes apoptosis through regulation of the expression of stanniocalcin-1. Oncol Rep. 2016;35:552–8.

    CAS  PubMed  Google Scholar 

  31. Yan Y, Wang Y, Xiong Y, Lin X, Zhou P, Chen Z. Reduced Klotho expression contributes to poor survival rates in human patients with ovarian cancer, and overexpression of Klotho inhibits the progression of ovarian cancer partly via the inhibition of systemic inflammation in nude mice. Mol Med Rep. 2017;15:1777–85.

    CAS  PubMed  Google Scholar 

  32. Gigante M, Lucarelli G, Divella C, Netti GS, Pontrelli P, Cafiero C, et al. Soluble serum αKlotho is a potential predictive marker of disease progression in clear cell renal cell carcinoma. Medicine. 2015;94:e1917.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Li XX, Huang LY, Peng JJ, Liang L, Shi DB, Zheng HT, et al. Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. Int J Oncol. 2014;45:611–8.

    PubMed  Google Scholar 

  34. Zhu H, Gao Y, Zhu S, Cui Q, Du J. Klotho improves cardiac function by suppressing reactive oxygen species (ROS) mediated apoptosis by modulating Mapks/Nrf2 signaling in doxorubicin-induced cardiotoxicity. Med Sci Monit. 2017;23:5283–93.

    PubMed  PubMed Central  Google Scholar 

  35. Mytych J, Solek P, Koziorowski M. Klotho modulates ER-mediated signaling crosstalk between prosurvival autophagy and apoptotic cell death during LPS challenge. Apoptosis. 2019;24:95–107.

    CAS  PubMed  Google Scholar 

  36. Cui W, Leng B, Wang G. Klotho protein inhibits H2O2-induced oxidative injury in endothelial cells via regulation of PI3K/AKT/Nrf2/HO-1 pathways. Can J Physiol Pharmacol. 2019;97:370–6.

    CAS  PubMed  Google Scholar 

  37. Bates GW, Bowling M. Physiology of the female reproductive axis. Periodontol. 2013;61:89–102.

    Google Scholar 

  38. Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med. 2010;363:365–71.

    CAS  PubMed  Google Scholar 

  39. Toyama R, Fujimori T, Nabeshima Y, Itoh Y, Tsuji Y, Osamura RY, et al. Impaired regulation of gonadotropins leads to the atrophy of the female reproductive system in klotho-deficient mice. Endocrinology. 2006;147:120–9.

    CAS  PubMed  Google Scholar 

  40. Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, et al. Timing and completion of puberty in female mice depend on estrogen receptor alpha-signaling in kisspeptin neurons. Proc Natl Acad Sci U S A. 2010;107:22693–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med. 2013;19:1153–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shahmoon S, Rubinfeld H, Wolf I, Cohen ZR, Hadani M, Shimon I, et al. The aging suppressor klotho: a potential regulator of growth hormone secretion. Am J Physiol Endocrinol Metab. 2014;307:E326–34.

    CAS  PubMed  Google Scholar 

  43. Weall BM, Al-Samerria S, Conceicao J, Yovich JL, Almahbobi G. A direct action for GH in improvement of oocyte quality in poor-responder patients. Reproduction. 2015;149:147–54.

    CAS  PubMed  Google Scholar 

  44. Ipsa E, Cruzat VF, Kagize JN, Yovich JL, Keane KN. Growth hormone and insulin-like growth factor action in reproductive tissues. Front Endocrinol. 2019;10:777.

    Google Scholar 

  45. Xu C, Messina A, Somm E, Miraoui H, Kinnunen T, Acierno JJ, et al. KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. Embo Mol Med. 2017;9:1379–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lund C, Pulli K, Yellapragada V, Giacobini P, Lundin K, Vuoristo S, et al. Development of gonadotropin-releasing hormone-secreting neurons from human pluripotent stem cells. Stem Cell Rep. 2016;7:149–57.

    CAS  Google Scholar 

  47. Poliandri A, Miller D, Howard S, Nobles M, Ruiz-Babot G, Harmer S, et al. Generation of kisspeptin-responsive GnRH neurons from human pluripotent stem cells. Mol Cell Endocrinol. 2017;447:12–22.

    CAS  PubMed  Google Scholar 

  48. Clarke HJ. Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle. Wiley Interdiscip Rev Dev Biol. 2018;7.

  49. Ghahremani-Nasab M, Ghanbari E, Jahanbani Y, Mehdizadeh A, Yousefi M. Premature ovarian failure and tissue engineering. J Cell Physiol. 2020;235:4217–26.

    CAS  PubMed  Google Scholar 

  50. Giordano S, Garrett-Mayer E, Mittal N, Smith K, Shulman L, Passaglia C, et al. Association of BRCA1 mutations with impaired ovarian reserve: connection between infertility and breast/ovarian cancer risk. J Adolesc Young Adult Oncol. 2016;5:337–43.

    PubMed  PubMed Central  Google Scholar 

  51. Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010;28:240–4.

    CAS  PubMed  Google Scholar 

  52. Wang ET, Pisarska MD, Bresee C, Ida Chen Y, Lester J, Afshar Y, et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertil Steril. 2014;102:1723–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ben-Aharon I, Levi M, Margel D, Yerushalmi R, Rizel S, Perry S, et al. Premature ovarian aging in BRCA carriers: a prototype of systemic precocious aging? Oncotarget. 2018;9:15931–41.

    PubMed  PubMed Central  Google Scholar 

  54. Liu T, Liu Y, Huang Y, Chen J, Yu Z, Chen C, et al. miR-15b induces premature ovarian failure in mice via inhibition of α-Klotho expression in ovarian granulosa cells. Free Radic Biol Med. 2019;141:383–92.

    CAS  PubMed  Google Scholar 

  55. Lu J, Wang Z, Cao J, Chen Y, Dong Y. A novel and compact review on the role of oxidative stress in female reproduction. Reprod Biol Endocrinol. 2018;16:80.

    PubMed  PubMed Central  Google Scholar 

  56. Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta. 1813;2011:1938–45.

    Google Scholar 

  57. Ma M, Chen XY, Gu C, Xiao XR, Guo T, Li B. Biochemical changes of oxidative stress in premature ovarian insufficiency induced by tripterygium glycosides. Int J Clin Exp Pathol. 2014;7:8855–61.

    PubMed  PubMed Central  Google Scholar 

  58. Kumar M, Pathak D, Venkatesh S, Kriplani A, Ammini AC, Dada R. Chromosomal abnormalities & oxidative stress in women with premature ovarian failure (POF). Indian J Med Res. 2012;135:92–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chang EM, Lim E, Yoon S, Jeong K, Bae S, Lee DR, et al. Cisplatin induces overactivation of the dormant primordial follicle through PTEN/AKT/FOXO3a pathway which leads to loss of ovarian reserve in mice. PLoS One. 2015;10:e144245.

    Google Scholar 

  60. John GB, Shidler MJ, Besmer P, Castrillon DH. Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation. Dev Biol. 2009;331:292–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Jin J, Jin L, Lim SW, Yang CW. Klotho deficiency aggravates tacrolimus-induced renal injury via the phosphatidylinositol 3-kinase-Akt-forkhead box protein O pathway. Am J Nephrol. 2016;43:357–65.

    CAS  PubMed  Google Scholar 

  62. Jiang L, Zhang X, Zheng X, Ru A, Ni X, Wu Y, et al. Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: implications for diabetic intervertebral disc degeneration. J Orthop Res. 2013;31:692–702.

    CAS  PubMed  Google Scholar 

  63. Li X, Feng Y, Lin JF, Billig H, Shao R. Endometrial progesterone resistance and PCOS. J Biomed Sci. 2014;21:2.

    PubMed  PubMed Central  Google Scholar 

  64. Mao Z, Fan L, Yu Q, Luo S, Wu X, Tang J, et al. Abnormality of Klotho signaling is involved in polycystic ovary syndrome. Reprod Sci. 2018;25:372–83.

    CAS  Google Scholar 

  65. Hsieh M, Johnson MA, Greenberg NM, Richards JS. Regulated expression of Wnts and Frizzleds at specific stages of follicular development in the rodent ovary. Endocrinology. 2002;143:898–908.

    CAS  PubMed  Google Scholar 

  66. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4:68–75.

    PubMed  PubMed Central  Google Scholar 

  67. You L, He B, Uematsu K, Xu Z, Mazieres J, Lee A, et al. Inhibition of Wnt-1 signaling induces apoptosis in beta-catenin-deficient mesothelioma cells. Cancer Res. 2004;64:3474–8.

    CAS  PubMed  Google Scholar 

  68. Ma X, Bai Y. IGF-1 activates the P13K/AKT signaling pathway via upregulation of secretory clusterin. Mol Med Rep. 2012;6:1433–7.

    CAS  PubMed  Google Scholar 

  69. Chong ZZ, Li F, Maiese K. Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways. Cell Signal. 2007;19:1150–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Hsu S, Huang S, Lin S, Ka S, Chen A, Shih M, et al. Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway. Biochem J. 2014;464:221–9.

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (grant nos. 91949114, 81722011, and 81521003), the Presidential Foundation of Nanfang Hospital, China (grant nos. 2018A002 and 2018C037), and the Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110105004).

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  1. Tingting Xie and Wenting Ye contributed equally to this work. Correspondance to: Yali Song. E-mail: syl@smu.edu.cn; and Lili Zhou. E-mail: jinli730@smu.edu.cn 

Authors and Affiliations

  1. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China

    Tingting Xie, Wenting Ye, Jing Liu & Yali Song

  2. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave., Guangzhou, 510515, China

    Wenting Ye & Lili Zhou

  3. Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China

    Lili Zhou

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  1. Tingting Xie
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All authors contributed in drafting the manuscript and provided approval for the version to be published. All authors agreed to be accountable for all aspects of the review.

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Xie, T., Ye, W., Liu, J. et al. The Emerging Key Role of Klotho in the Hypothalamus–Pituitary–Ovarian Axis. Reprod. Sci. 28, 322–331 (2021). https://doi.org/10.1007/s43032-020-00277-5

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