Skip to main content
SpringerLink
Log in

Expression and tissue localization of renalase, a novel soluble FAD-dependent protein, in reproductive/steroidogenic systems

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Renalase was initially identified in human kidney as a soluble monoamine oxidase. Here we show that renalase is predominantly expressed in reproductive/steroidogenic systems, with particularly substantial expression in oocytes, granulosa, interstitial and luteal cells of ovary, spermatogenic cells of testis, and cortex of adrenal gland, suggesting its function(s) in maturation of germ cells and steroid hormone regulation. Renalase expression increases in testes and ovaries as mice develop and its expression is further enhanced in the ovaries of pregnant mice, indicating an activity of renalase in reproduction. Gonadotropin-releasing hormone (GnRH) antagonist, cetrorelix, repressed renalase expression in mice ovaries and testes, suggesting that steroids regulate renalase expression. Leptin is an effector and modulator of steroid hormones and reproduction. Surprisingly, knockout of leptin causes a dramatic increase of renalase expression in mice testes. Taken together, our results suggest that reproductive/steroidogenic systems are also the sources for renalase secretion and renalase may play a critical role in reproduction and hormone regulation. This provides a novel insight into understanding the function of renalase.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

NA:

Noradrenaline

ADR:

Adrenaline

DA:

Dopamine

FAD:

Flavin adenine dinucleotide

ESRD:

End-stage renal disease

GnRH:

Gonadotropin-releasing hormone

ob/ob:

Leptin knockout

IHC:

Immunohistochemistry

LH:

Luteinizing hormone

FSH:

Follicle-stimulating hormone

LEPR:

Leptin receptor

References

  1. Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, Wu Y, Peixoto A, Crowley S, Desir GV (2005) Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest 115(5):1275–1280. doi:10.1172/JCI24066

    PubMed  CAS  Google Scholar 

  2. Boomsma F, Tipton KF (2007) Renalase, a catecholamine-metabolising enzyme? J Neural Transm 114(6):775–776. doi:10.1007/s00702-007-0672-1

    Article  PubMed  CAS  Google Scholar 

  3. Xu J, Desir GV (2007) Renalase, a new renal hormone: its role in health and disease. Curr Opin Nephrol Hypertens 16(4):373–378. doi:10.1097/MNH.0b013e3281bd8877

    Article  PubMed  CAS  Google Scholar 

  4. Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, Desir GV (2008) Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation 117(10):1277–1282. doi:10.1161/CIRCULATIONAHA.107.732032

    Article  PubMed  CAS  Google Scholar 

  5. Desir GV (2007) Renalase is a novel renal hormone that regulates cardiovascular function. J Am Soc Hypertens 1(2):99–103. doi:10.1016/j.jash.2006.12.001

    Article  PubMed  Google Scholar 

  6. Pandini V, Ciriello F, Tedeschi G, Rossoni G, Zanetti G, Aliverti A (2010) Synthesis of human renalase1 in Escherichia coli and its purification as a FAD-containing holoprotein. Protein Expr Purif 72(2):244–253. doi:10.1016/j.pep.2010.03.008

    Article  PubMed  CAS  Google Scholar 

  7. Milani M, Ciriello F, Baroni S, Pandini V, Canevari G, Bolognesi M, Aliverti A (2011) FAD-binding site and NADP reactivity in human renalase: a new enzyme involved in blood pressure regulation. J Mol Biol 411(2):463–473. doi:10.1016/j.jmb.2011.06.010

    Article  PubMed  CAS  Google Scholar 

  8. Zhao Q, Fan Z, He J, Chen S, Li H, Zhang P, Wang L, Hu D, Huang J, Qiang B, Gu D (2007) Renalase gene is a novel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population. J Mol Med 85(8):877–885. doi:10.1007/s00109-006-0151-4

    Article  PubMed  CAS  Google Scholar 

  9. Wang J, Qi S, Cheng W, Li L, Wang F, Li YZ, Zhang SP (2008) Identification, expression and tissue distribution of a renalase homologue from mouse. Mol Biol Rep 35(4):613–620. doi:10.1007/s11033-007-9131-1

    Article  PubMed  CAS  Google Scholar 

  10. Hennebry SC, Eikelis N, Socratous F, Desir G, Lambert G, Schlaich M (2010) Renalase, a novel soluble FAD-dependent protein, is synthesized in the brain and peripheral nerves. Mol Psychiatry 15(3):234–236. doi:10.1038/mp.2009.74 mp200974 [pii]

    Article  PubMed  CAS  Google Scholar 

  11. Meirow D, Assad G, Dor J, Rabinovici J (2004) The GnRH antagonist cetrorelix reduces cyclophosphamide-induced ovarian follicular destruction in mice. Hum Reprod 19(6):1294–1299. doi:10.1093/humrep/deh257

    Article  PubMed  CAS  Google Scholar 

  12. Di Cristo C, De Lisa E, Di Cosmo A (2009) Control of GnRH expression in the olfactory lobe of Octopus vulgaris. Peptides 30(3):538–544. doi:10.1016/j.peptides.2008.07.007

    Article  PubMed  Google Scholar 

  13. Madgwick S, Bagu ET, Duggavathi R, Bartlewski PM, Barrett DM, Huchkowsky S, Cook SJ, Beard AP, Rawlings NC (2008) Effects of treatment with GnRH from 4 to 8 weeks of age on the attainment of sexual maturity in bull calves. Anim Reprod Sci 104(2–4):177–188. doi:10.1016/j.anireprosci.2007.02.013

    Article  PubMed  CAS  Google Scholar 

  14. Smith CC, Mocanu MM, Davidson SM, Wynne AM, Simpkin JC, Yellon DM (2006) Leptin, the obesity-associated hormone, exhibits direct cardioprotective effects. Br J Pharmacol 149(1):5–13. doi:10.1038/sj.bjp.0706834

    Article  PubMed  CAS  Google Scholar 

  15. Di Carlo C (2003) Leptin and female reproduction. J Endocrinol Invest 26(1):93–95

    PubMed  Google Scholar 

  16. Holness MJ, Munns MJ, Sugden MC (1999) Current concepts concerning the role of leptin in reproductive function. Mol Cell Endocrinol 157(1–2):11–20

    Article  PubMed  CAS  Google Scholar 

  17. Magni P, Motta M, Martini L (2000) Leptin: a possible link between food intake, energy expenditure, and reproductive function. Regul Pept 92(1–3):51–56

    Article  PubMed  CAS  Google Scholar 

  18. Smith GD, Jackson LM, Foster DL (2002) Leptin regulation of reproductive function and fertility. Theriogenology 57(1):73–86

    Article  PubMed  CAS  Google Scholar 

  19. Chehab FF, Lim ME, Lu R (1996) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 12(3):318–320. doi:10.1038/ng0396-318

    Article  PubMed  CAS  Google Scholar 

  20. Roberts AJ, McLean DJ (2011) Differential gene expression in anterior pituitary glands from anestrous and cycling postpartum beef cows. J Anim Sci 89(4):1035–1041. doi:10.2527/jas.2010-3433

    Article  PubMed  CAS  Google Scholar 

  21. Paulis L, Unger T (2010) Novel therapeutic targets for hypertension. Nat Rev Cardiol 7(8):431–441. doi:10.1038/nrcardio.2010.85

    Article  PubMed  CAS  Google Scholar 

  22. Tandler R, Kondruweit M, Fischlein T, Weyand M (2003) Hormone therapy in men-increased risk of cardiac allograft rejection? J Heart Lung Transplant 22(7):831–832

    Article  PubMed  CAS  Google Scholar 

  23. Nagatani S, Guthikonda P, Thompson RC, Tsukamura H, Maeda KI, Foster DL (1998) Evidence for GnRH regulation by leptin: leptin administration prevents reduced pulsatile LH secretion during fasting. Neuroendocrinology 67(6):370–376

    Article  PubMed  CAS  Google Scholar 

  24. Hausman GJ, Barb CR (2010) Adipose tissue and the reproductive axis: biological aspects. Endocr Dev 19:31–44. doi:10.1159/000316895

    Article  PubMed  CAS  Google Scholar 

  25. Loucks AB (2007) Energy availability and infertility. Curr Opin Endocrinol Diabetes Obes 14(6):470–474. doi:10.1097/MED.0b013e3282f1cb6a01266029-200712000-00009

    Article  PubMed  Google Scholar 

  26. Barkan D, Hurgin V, Dekel N, Amsterdam A, Rubinstein M (2005) Leptin induces ovulation in GnRH-deficient mice. FASEB J 19(1):133–135. doi:10.1096/fj.04-2271fje

    PubMed  CAS  Google Scholar 

  27. Gueorguiev M, Goth ML, Korbonits M (2001) Leptin and puberty: a review. Pituitary 4(1–2):79–86

    Article  PubMed  CAS  Google Scholar 

  28. Sone M, Osamura RY (2001) Leptin and the pituitary. Pituitary 4(1–2):15–23

    Article  PubMed  CAS  Google Scholar 

  29. Caprio M, Fabbrini E, Isidori AM, Aversa A, Fabbri A (2001) Leptin in reproduction. Trends Endocrinol Metab 12(2):65–72

    Article  PubMed  CAS  Google Scholar 

  30. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS (1997) Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99(3):391–395. doi:10.1172/JCI119172

    Article  PubMed  CAS  Google Scholar 

  31. Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG Jr (2011) Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152(6):2302–2310. doi:10.1210/en.2011-0096

    Article  PubMed  CAS  Google Scholar 

  32. Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE, Grattan DR, Anderson GM (2009) Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 150(6):2805–2812. doi:10.1210/en.2008-1693

    Article  PubMed  CAS  Google Scholar 

  33. Sairam MR, Wang M, Danilovich N, Javeshghani D, Maysinger D (2006) Early obesity and age-related mimicry of metabolic syndrome in female mice with sex hormonal imbalances. Obesity (Silver Spring) 14(7):1142–1154. doi:10.1038/oby.2006.131

    Article  CAS  Google Scholar 

  34. Xu ZP, Wawrousek EF, Piatigorsky J (2002) Transketolase haploinsufficiency reduces adipose tissue and female fertility in mice. Mol Cell Biol 22(17):6142–6147

    Article  PubMed  CAS  Google Scholar 

  35. Chehab FF (1996) A broader role for leptin. Nat Med 2(7):723–724

    Article  PubMed  CAS  Google Scholar 

  36. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O’Rahilly S (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 356(3):237–247. doi:10.1056/NEJMoa063988

    Article  PubMed  CAS  Google Scholar 

  37. Quennell JH, Howell CS, Roa J, Augustine RA, Grattan DR, Anderson GM (2011) Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology 152(4):1541–1550. doi:10.1210/en.2010-1100

    Article  PubMed  CAS  Google Scholar 

  38. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL et al (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334(5):292–295. doi:10.1056/NEJM199602013340503

    Article  PubMed  CAS  Google Scholar 

  39. Houseknecht KL, Portocarrero CP (1998) Leptin and its receptors: regulators of whole-body energy homeostasis. Domest Anim Endocrinol 15(6):457–475

    Article  PubMed  CAS  Google Scholar 

  40. 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. doi:10.1038/372425a0

    Article  PubMed  CAS  Google Scholar 

  41. Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395(6704):763–770. doi:10.1038/27376

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We appreciate the personal communication with Prof. Gary Desir (Yale School of Medicine, USA). We also thank Shaoyong Chen (BIDMC, Harvard Medical School, USA) for reviewing our manuscript and Prof. Peng Li (School of Life Sciences, Tsinghua University, China) for the help with the ob/ob mice tissue.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding

This work was supported by the grants from the National Natural Science Foundation of China (81171063, J1030622) and National Key Projects of Ministry of Agriculture of China (2011ZX08011-006).

Author information

Author notes

  1. Mingxue Zhou

    Present address: Beijing Hospital of TCM Affiliated with Capital Medical University, Beijing Institute of TCM, Beijing, 100010, China

Authors and Affiliations

  1. State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing, China

    Mingxue Zhou, Tong Liang, Yifeng Wang, Da Jin, Jian Wang, Liyun Jia & Shuping Zhang

Authors
  1. Mingxue Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tong Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yifeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Da Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liyun Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shuping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuping Zhang.

Additional information

Mingxue Zhou and Tong Liang contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 3931 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, M., Liang, T., Wang, Y. et al. Expression and tissue localization of renalase, a novel soluble FAD-dependent protein, in reproductive/steroidogenic systems. Mol Biol Rep 40, 3987–3994 (2013). https://doi.org/10.1007/s11033-012-2476-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-2476-0

Keywords

Search

Navigation