Distribution of progesterone receptors and the membrane component of progesterone receptor in various organs and tissues of male and female rats

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Abstract

Progesterone regulates reproductive processes and affects many functions of various non-reproductive organs. Its effects in mammals and humans are mediated by nuclear (nPRs) and membrane progesterone receptors (mPRs). The action of progesterone through different types of receptors may differ significantly and has tissue specific features. The expression of known types and subtypes of progesterone receptors in the tissues of male and female rats has been studied fragmentarily. The purpose of our work was to study the expression of five mPRs genes, as well as the nPRs gene and the membrane component of the progesterone receptor PGRMC I in the reproductive organs and in 17 non-reproductive tissues of male and female rats using reverse transcription followed by real-time PCR. In this study, it was shown that a high level of nPRs gene expression in rats is found not only in reproductive organs of females (uterus, ovary, mammary glands), but also in seminal vesicles of males, in the brain and trachea of both sexes, in blood vessels, and in the pancreas of females. The highest level of expression of mPRs genes of all subtypes was found in the testes, while expression of the gene encoding nPRs was practically undetectable in them. Expression of genes encoding mPRs was also detected in the liver and spleen of male and female rats, while expression of the gene encoding nPRs was at background levels. Virtually no expression of nPRs, mPRs, and membrane component of progesterone receptor (PGRMC I) genes was detected in muscle, and its level was very low in the heart in animals of both sexes. We found sex-specific differentiation of nuclear and membrane receptor mRNA levels in rats in non-reproductive tissues, characterized by a predominance of nPRs transcripts and three subtypes of mPRs (α, β, δ) in females and two subtypes of mPRs (γ, ε) in males. Data on the presence of progesterone receptors in tissues not involved in reproduction confirm the effect of progesterone on these organs. High levels of mRNA for various progesterone receptors in the tissues of male rats, such as the pancreas, lungs, kidney, and trachea, indicate an important physiological role of progestins not only in females, but also in males, which is still poorly understood. The work also discusses the known functions of progesterone receptors in the tissues studied.

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About the authors

A. D. Dmitrieva

Lomonosov Moscow State University

Email: schelkunova-t@mail.ru

Biological Department

Russian Federation, Moscow, 119991

I. A. Morozov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119991

A. M. Karhov

Lomonosov Moscow State University

Email: schelkunova-t@mail.ru

Biological Department

Russian Federation, Moscow, 119991

P. M. Rubtsov

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: schelkunova-t@mail.ru
Russian Federation, Moscow, 119991

O. V. Smirnova

Lomonosov Moscow State University

Email: schelkunova-t@mail.ru

Biological Department

Russian Federation, Moscow, 119991

T. A. Shchelkunova

Lomonosov Moscow State University

Author for correspondence.
Email: schelkunova-t@mail.ru

Biological Department

Russian Federation, Moscow, 119991

References

  1. Guennoun R., Labombarda F., Gonzalez Deniselle M.C., Liere P., De Nicola A.F., Schumacher M. 2015. Progesterone and allopregnanolone in the central nervous system: Response to injury and implication for neuroprotection. J. Steroid Biochem. Mol. Biol. 146, 48–61. https://doi.org/10.1016/j.jsbmb.2014.09.001
  2. González-Orozco J.C., Camacho-arroyo I. 2019. Progesterone actions during central nervous system development. Front. Neurosci. 13, 503. https://doi.org/10.3389/fnins.2019.00503.
  3. Schuffner A.A., Bastiaan H.S., Duran H.E., Lin Z.Y., Morshedi M., Franken D.R., Oehninger S. 2002. Zona pellucida-induced acrosome reaction in human sperm: Dependency on activation of pertussis toxin-sensitive G(i) protein and extracellular calcium, and priming effect of progesterone and follicular fluid. Mol. Hum. Reprod. 8, 722–727. https://doi.org/10.1093/molehr/8.8.722.
  4. Oettel M., Mukhopadhyay A.K. 2004. Progesterone: The forgotten hormone in men? Aging Male 7, 236–257. https://doi.org/10.1080/13685530400004199.
  5. Polikarpova A.V., Levina I.S., Sigai N.V., Zavarzin I.V., Morozov I.A., Rubtsov P.M., Guseva A.A., Smirnova O.V., Shchelkunova T.A. 2019. Immunomodulatory effects of progesterone and selective ligands of membrane progesterone receptors. Steroids. 145, 5–18. https://doi.org/10.1016/j.steroids.2019.02.009.
  6. Stelmanska E., Szrok S., Swierczynski J. 2015. Progesterone-induced down-regulation of hormone sensitive lipase (Lipe) and up-regulation of G0/G1 switch 2 (G0s2) genes expression in inguinal adipose tissue of female rats is reflected by diminished rate of lipolysis. J. Steroid Biochem. Mol. Biol. 147, 31–39. https://doi.org/10.1016/j.jsbmb.2014.11.017.
  7. Seifert-Klauss V., Prior J.C. 2010 Progesterone and bone: Actions promoting bone health in women. J. Osteoporos. 2010, 845180. https://doi.org/10.4061/2010/845180.
  8. Щелкунова Т.А., Морозов И.А. 2015. Молекулярные основы и тканевая специфичность действия прогестинов. Мол. биол. 49, 728–748. http://doi.org/10.7868/S0026898415050158.
  9. Zhu Y., Bond J., Thomas P. 2003. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc. Natl. Acad. Sci. USA. 100, 2237–2242. https://doi.org/10.1073/pnas.0436133100.
  10. Pang Y., Dong J., Thomas P. 2013. Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and ε (mPRδ and mPRε) and mPRδ involvement in neurosteroid inhibition of apoptosis. Endocrinology. 154, 283–295. https://doi.org/10.1210/en.2012–1772.
  11. Thomas P., Pang Y., Dong J. 2014. Enhancement of cell surface expression and receptor functions of membrane progestin receptor α (mPRα) by progesterone receptor membrane component 1 (PGRMC I): Evidence for a role of PGRMC I as an adaptor protein for steroid receptors. Endocrinology. 155, 1107–1119. https://doi.org/10.1210/en.2013–1991.
  12. Sleiter N., Pang Y., Park C., Horton T.H., Dong J., Tomas P., Levine J.E. 2009. Progesterone receptor A (PRA) and PRB independent effects of progesterone on gonadotropin releasing hormone release. Endocrinology. 150, 3833–3844. https://doi.org/10.1210/en.2008–0774.
  13. Camilletti M.A., Abeledo-Machado A., Perez P.A., Faraoni E.Y., De Fino F., Rulli S.B., Ferraris J., Pisera D., Gutierrez S., Thomas P., Díaz-Torga G. 2019. mPRs represent a novel target for PRL inhibition in experimental prolactinomas. Endocr. Relat. Cancer. 26, 1–14. https://doi.org/10.1530/ERC-18–0409.
  14. Flock G.B., Cao X., Maziarz M., Drucker D.J. 2013. Activation of enteroendocrine membrane progesterone receptors promotes incretin secretion and improves glucose tolerance in mice. Diabetes. 62, 283–290. https://doi.org/10.2337/db12–0601.
  15. Tan W., Pang Y., Tubbs C., Thomas P. 2019. Induction of sperm hypermotility through membrane progestin receptor alpha (mPRα): A teleost model of rapid, multifaceted, nongenomic progestin signaling. Gen. Comp. Endocrinol. 279, 60–66. https://doi.org/10.1016/j.ygcen.2018.12.002.
  16. Karteris E., Zervou S., Pang Y., Dong J., Hillhouse E.W., Randeva H.S., Thomas P. 2006. Progesterone signaling in human myometrium through two novel membrane G protein coupled receptors: Potential role in functional progesterone withdrawal at term. Mol. Endocrinol. 20, 1519–1534. https://doi.org/10.1210/me.2005–0243.
  17. Pang Y., Dong J., Thomas P. 2015. Progesterone increases nitric oxide synthesis in human vascular endothelial cells through activation of membrane progesterone receptor-α. Am. J. Physiol. Endocrinol. Metab. 308, E899–E911. https://doi.org/10.1152/ajpendo.00527.2014.
  18. Щелкунова Т.А., Морозов И.А. 2016. Прогестины и канцерогенез. Мол. биол. 2016. 50, 10–26. http://doi.org/ 10.7868/S0026898416010171.
  19. Dosiou C., Hamilton A.E., Pang Y., Overgaard M.T., Tulac S., Dong J., Thomas P., Giudice L.C. 2008. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J. Endocrinol. 196, 67–77. https://doi.org/10.1677/JOE-07–0317.
  20. Frye C.A., Walf A.A., Kohtz A.S., Zhu Y. 2013. Membrane progestin receptors in the midbrain ventral tegmental area are required for progesterone-facilitated lordosis of rats. Horm. Behav. 64, 539–545. https://doi.org/10.1016/j.yhbeh.2013.05.012.
  21. Zuloaga D.G., Yahn S.L., Pang Y., Quihuis A.M., Oyola M.G., Reyna A., Thomas P., Handa R.J., Mani S.K. 2012. Distribution and estrogen regulation of membrane progesterone receptor-β in the female rat brain. Endocrinology. 153, 4432–4443. https://doi.org/10.1210/en.2012–1469.
  22. Intlekofer K.A., Petersen S.L. 2011. Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience. 172, 55–65. https://doi.org/10.1016/j.neuroscience.2010.10.051.
  23. Petersen S.L., Intlekofer K.A., Moura-Conlon P.J., Brewer D.N., Del Pino Sans J., Lopez J.A. 2013. Novel progesterone receptors: Neural localization and possible functions. Front. Neurosci. 7, 164. https://doi.org/10.3389/fnins.2013.00164.
  24. Cai Z., Stocco C. 2005. Expression and regulation of progestin membrane receptors in the rat corpus luteum. Endocrinology. 146, 5522–5532. https://doi.org/10.1210/en.2005–0759.
  25. Yoshida A., Yasuda K., Okada H. 2024. Changes in the conflicting nongenomic effects of progesterone in rat myometrium during pregnancy. Life Sci. 340, 122454. https://doi.org/10.1016/j.lfs.2024.122454.
  26. Livak K.J., Schmittgen T.D. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT method. Methods. 25, 402–408. https://doi.org/10.1006/meth.2001.1262.
  27. Svingen T., Letting H., Hadrup N., Hass U., Vinggaard A.M. 2015. Selection of reference genes for quantitative RT-PCR (RT-qPCR) analysis of rat tissues under physiological and toxicological conditions. PeerJ. 24, e855. https://doi.org/10.7717/peerj.855.
  28. Liman S.V., Kara C.O., Bir F., Yildirim B., Topcu S., Sahin B. 2005. The effects of estradiol and progesterone on the synthesis of collagen in tracheal surgery. Int. J. Pediatr. Otorhinolaryngol. 69, 1327–1331. https://doi.org/10.1016/j.ijporl.2005.03.028.
  29. Pang Y., Thomas P. 2018. Progesterone induces relaxation of human umbilical cord vascular smooth muscle cells through mPRα (PAQR7). Mol. Cell. Endocrinol. 474, 20–34. https://doi.org/10.1016/j.mce.2018.02.003.
  30. Pang Y., Thomas P. 2019. Role of mPRα (PAQR7) in progesterone-induced Ca2+ decrease in human vascular smooth muscle cells. J. Mol. Endocrinol. 63, 199–213. https://doi.org/10.1530/JME-19–0019.
  31. Pang Y., Thomas P. 2021. Involvement of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) in mPRα (PAQR7)-mediated progesterone induction of vascular smooth muscle relaxation. Am. J. Physiol. Endocrinol. Metabol. 320, E453–E466. https://doi.org/10.1152/ajpendo.00359.2020.
  32. Straub S.G., Sharp G.W., Meglasson M.D., De Souza C.J. 2002. Progesterone inhibits insulin secretion by a membrane delimited, non-genomic action. Biosci. Rep. 21, 653–666. https://doi.org/10.1023/A:1014773010350.
  33. Charles N.J., Thomas P., Lange C.A. 2010. Expression of membrane progesterone receptors (mPR/PAQR) in ovarian cancer cells: implications for progesterone induced signaling events. Horm. Cancer. 1, 167–176. https://doi.org/10.1007/s12672–010–0023–9.
  34. Nieuwenhuizen A.G., Schuiling G.A., Liem S.M.S., Moes H., Koiter T.R., Uilenbroek J.T. 1999. Progesterone stimulates pancreatic cell proliferation in vivo. Eur. J. Endocrinol. 140, 256–263. https://doi.org/10.1530/eje.0.1400256.
  35. Piccinato C.A., Rosa G.J.M., N'jai A.U., Jefcoate C.R., Wiltbank M.C. 2013. Estradiol and progesterone exhibit similar patterns of hepatic gene expression regulation in the bovine model. PLoS One. 17, e73552. https://doi.org/10.1371/journal.pone.0073552.
  36. Magkos F., Mittendorfer B. 2009. Gender differences in lipid metabolism and the effect of obesity. Obstet Gynecol. Clin. North Am. 36, 245–265. https://doi.org/10.1016/j.ogc.2009.03.001.
  37. Mackern-Oberti J.P., Jara, E.L., Riedel C.A., Kalergis A.M. 2017. Hormonal modulation of dendritic cells differentiation, maturation and function: Implications for the initiation and progress of systemic autoimmunity. Arch. Immunol. Ther. Exp. (Warsz). 65, 123–136. https://doi.org/10.1007/s00005–016–0418–6.
  38. Yang L., Li X., Zhao J., Hou Y. 2006. Progesterone is involved in the maturation of murine spleen CD11c-positive dendritic cells. Steroids. 71, 922–929. https://doi.org/10.1016/j.steroids.2006.07.001.
  39. Packhäuser K.R.H., Roman-Sosa G., Ehrhardt J., Krüger D., Zygmunt M., Muzzio D.O. 2017. A kinetic study of CD83 reveals an upregulation and higher production of sCD83 in lymphocytes from pregnant mice. Front. Immunol. 8, 486. https://doi.org/10.3389/fimmu.2017.00486.
  40. Stanojević S., Kovačević-Jovanović V., Dimitrijević M., Vujić V., Ćuruvija I., Blagojević V., Leposavić G. 2015. Unopposed estrogen supplementation/progesterone deficiency in post-reproductive age affects the secretory profile of resident macrophages in a tissue-specific manner in the rat. Am. J. Reprod. Immunol. 74, 445–456. https://doi.org/10.1111/aji.12424.
  41. Sharif M., Kerns K., Sutovsky P., Bovin N., Miller D.J. 2021. Progesterone induces porcine sperm release from oviduct glycans in a proteasome-dependent manner. Reproduction. 161, 449–457. https://doi.org/10.1530/REP-20–0474.
  42. Mirihagalle S., Hughes J.R., Miller D.J. 2022. Progesterone-induced sperm release from the oviduct sperm reservoir. Cells. 11, 1622. https://doi.org/10.3390/cells11101622.
  43. Cai X., Clapham D.E. 2008. Evolutionary genomics reveals lineage-specific gene loss and rapid evolution of a sperm-specific ion channel complex: CatSpers and CatSperβ. PLoS One. 3, e3569. https://doi.org/10.1371/journal.pone.0003569.
  44. Thomas P., Tubbs C., Garry V. F. 2009. Progestin functions in vertebrate gametes mediated by membrane progestin receptors (mPRs): Identification of mPRα on human sperm and its association with sperm motility. Steroids. 74, 614–621. https://doi.org/10.1016/j.steroids.2008.10.020.
  45. de Vries G.J., Forger N.G. 2015. Sex differences in the brain: a whole body perspective. Biol. Sex Differ. 6, 15. https://doi.org/10.1186/s13293–015–0032-z.
  46. Thomas P., Pang Y., Camilletti, M.A., Castelnovo L.F 2022. Functions of membrane progesterone receptors (mPRs, PAQRs) in nonreproductive tissues. Endocrinology. 163, bqac147. https://doi.org/10.1210/endocr/bqac147.
  47. Patra P.B, Patra S. 2013. Sex differences in the physiology and pharmacology of the lower urinary tract. Curr. Urol. 6, 179–188. https://doi.org/10.1159/000343536.
  48. Patra P.B., Thorneloe K.S., Laping N.J. 2009. Effect of estrogen and progesterone on urodynamics in conscious rat. Urology. 74, 463–466. https://doi.org/10.1016/j.urology.2008.12.046.
  49. Chen J., Zhou Y.X., Yu Y.L., Shen Z.J. 2008. Effects of sex hormones on bladder function and structure: Experiment with ovariectomized female rats. Zhonghua Yi Xue Za Zhi. 88, 1851–1854, Chinese. https://doi.org/10.3321/j.issn:0376–2491.2008.26.014.
  50. Rojas-Vega L., Reyes-Castro L.A., Ramírez V., Bautista-Pérez R., Rafael C., Castañeda-Bueno M., Meade P., de Los Heros P., Arroyo-Garza I., Bernard V., Binart N., Bobadilla N.A., Hadchouel J., Zambrano E., Gamba G. 2015. Ovarian hormones and prolactin increase renal NaCl cotransporter phosphorylation. Am. J. Physiol. Renal. Physiol. 308, F799–F808. https://doi.org/10.1152/ajprenal.00447.2014.
  51. Elabida B., Edwards A., Salhi A., Azroyan A., Fodstad H., Meneton P., Doucet A., Bloch-Faure M., Crambert G. 2011. Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium. Kidney Int. 80, 256–262. https://doi.org/10.1038/ki.2011.15.

Supplementary files

Supplementary Files
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2. Fig. 1. Expression level of nPRs mRNA in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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3. Fig. 2. Expression level of mPRα mRNA in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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4. Fig. 3. Expression level of mPRβ mRNA in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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5. Fig. 4. Expression level of mPRγ mRNA in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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6. Fig. 5. Expression level of mPRδ mRNA in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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7. Fig. 6. Expression level of mPRε mRNA in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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8. Fig. 7. PGRMC I mRNA expression levels in organs of male and female Wistar rats (non-reproductive tissues, n = 3, reproductive n = 5). Data are presented as mean ± standard deviation.

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9. Fig. 8. Expression levels of mPRs and PGRMC I mRNA in the liver and spleen of female and male Wistar rats (n = 3) and in the testes (n = 5). Data are presented as mean ± standard deviation.

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