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Iron is Responsible for Production of Reactive Oxygen Species Regulating Vasopressin Expression in the Mouse Paraventricular Nucleus

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Abstract

Reactive oxygen species (ROS) act as signaling molecules for maintaining homeostasis, particularly in the regulation of body-fluid balance in the paraventricular nucleus (PVN) of the hypothalamus. However, there has been little discussion regarding the source of ROS generation in this hypothalamic region. Because iron is the most abundant metal in the brain, we hypothesized that iron may act as a source of ROS, which regulate vasopressin (VP) expression. In the present study, we compared the amount of iron in the PVN to that in other forebrain regions of normal ICR mice, and examined the relationship among iron, ROS, and VP in the PVN of the iron-overloaded with iron dextran and iron-chelated mice with deferoxamine. The amount of iron in the PVN was significantly higher than in any of the forebrain regions we examined. The amount of iron in the PVN was significantly increased in iron-overloaded mice, although not in iron-chelated mice. These results suggest that the PVN exhibits high iron affinity. Both ROS production and VP expression in the PVN of iron-overloaded mice were significantly increased relative to levels observed in control mice. VP concentration in blood of iron-overloaded mice was also significantly higher than that of control mice. Interestingly, iron overload did not alter the expression of nitric oxide synthase, another modulator of VP expression. Taken together, our results suggest that high levels of iron in the PVN induce the production of ROS, which regulate VP expression, independent of nitric oxide signaling.

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References

  1. Pereira RD, De Long NE, Wang RC, Yazdi FT, Holloway AC, Raha S (2015) Angiogenesis in the placenta: the role of reactive oxygen species signaling. BioMed Res Int 2015:814543

    PubMed  PubMed Central  Google Scholar 

  2. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214

    Article  CAS  PubMed  Google Scholar 

  3. Waris G, Ahsan H (2006) Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 5:14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Poon HF, Calabrese V, Scapagnini G, Butterfield DA (2004) Free radicals: key to brain aging and heme oxygenase as a cellular response to oxidative stress. J Gerontol Ser A 59:478–493

    Article  Google Scholar 

  5. Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Benani A, Troy S, Carmona MC, Fioramonti X, Lorsignol A, Leloup C, Casteilla L, Penicaud L (2007) Role for mitochondrial reactive oxygen species in brain lipid sensing: redox regulation of food intake. Diabetes 56:152–160

    Article  CAS  PubMed  Google Scholar 

  7. Leloup C, Magnan C, Benani A, Bonnet E, Alquier T, Offer G, Carriere A, Periquet A, Fernandez Y, Ktorza A, Casteilla L, Penicaud L (2006) Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing. Diabetes 55:2084–2090

    Article  CAS  PubMed  Google Scholar 

  8. Abboud F, Floras J, Aylward P, Guo G, Gupta B, Schmid P (1990) Role of vasopressin in cardiovascular and blood pressure regulation. J Vasc Res 27:106–115

    Article  CAS  Google Scholar 

  9. Wang G, Coleman CG, Chan J, Faraco G, Marques-Lopes J, Milner TA, Guruju MR, Anrather J, Davisson RL, Iadecola C, Pickel VM (2013) Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons. Am J Physiol Regul Integr Comp Physiol 304:R1096–R1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xia H, Suda S, Bindom S, Feng Y, Gurley SB, Seth D, Navar LG, Lazartigues E (2011) ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS ONE 6:e22682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hidalgo C, Carrasco MA, Munoz P, Nunez MT (2007) A role for reactive oxygen/nitrogen species and iron on neuronal synaptic plasticity. Antioxid Redox Signal 9:245–255

    Article  CAS  PubMed  Google Scholar 

  12. Kishida KT, Klann E (2007) Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal 9:233–244

    Article  CAS  PubMed  Google Scholar 

  13. Yang Y, Bazhin AV, Werner J, Karakhanova S (2013) Reactive oxygen species in the immune system. Int Rev Immunol 32:249–270

    Article  CAS  PubMed  Google Scholar 

  14. Ji AR, Ku SY, Cho MS, Kim YY, Kim YJ, Oh SK, Kim SH, Moon SY, Choi YM (2010) Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. Exp Mol Med 42:175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Spooner R, Yilmaz O (2011) The role of reactive-oxygen-species in microbial persistence and inflammation. Int J Mol Sci 12:334–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gerlach M, Ben-Shachar D, Riederer P, Youdim MB (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases. J Neurochem 63:793–807

    Article  CAS  PubMed  Google Scholar 

  17. Kim JY, Lee EY, Sohn HJ, Kim DW, Cho SS, Seo JH (2014) Sequential accumulation of iron in glial cells during chicken cerebellar development. Acta Histochem 116:570–576

    Article  CAS  PubMed  Google Scholar 

  18. Jiang H, Luan Z, Wang J, Xie J (2006) Neuroprotective effects of iron chelator desferal on dopaminergic neurons in the substantia nigra of rats with iron-overload. Neurochem Int 49:605–609

    Article  CAS  PubMed  Google Scholar 

  19. Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74:199–205

    Article  CAS  PubMed  Google Scholar 

  20. Mesquita SD, Ferreira AC, Sousa JC, Santos NC, Correia-Neves M, Sousa N, Palha JA, Marques F (2012) Modulation of iron metabolism in aging and in alzheimer’s disease: relevance of the choroid plexus. Front Cell Neurosci 6:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. St-Louis R, Parmentier C, Grange-Messent V, Mhaouty-Kodja S, Hardin-Pouzet H (2014) Reactive oxygen species are physiological mediators of the noradrenergic signaling pathway in the mouse supraoptic nucleus. Free Radic Biol Med 71:231–239

    Article  CAS  PubMed  Google Scholar 

  22. Rotondo F, Butz H, Syro LV, Yousef GM, Di Ieva A, Restrepo LM, Quintanar-Stephano A, Berczi I, Kovacs K (2016) Arginine vasopressin (AVP): a review of its historical perspectives, current research and multifunctional role in the hypothalamo-hypophysial system. Pituitary 19:345–355

    Article  CAS  PubMed  Google Scholar 

  23. St-Louis R, Parmentier C, Raison D, Grange-Messent V, Hardin-Pouzet H (2012) Reactive oxygen species are required for the hypothalamic osmoregulatory response. Endocrinology 153:1317–1329

    Article  CAS  PubMed  Google Scholar 

  24. Hill JM, Switzer RC 3rd (1984) The regional distribution and cellular localization of iron in the rat brain. Neuroscience 11:595–603

    Article  CAS  PubMed  Google Scholar 

  25. Li C, Odagiri S, Meguro R, Asano Y, Shoumura K (2009) Nonheme-iron deposition in the hypothalamo-neurohypophyseal system of the rat brain. Hirosaki Med J 60:63–76

    CAS  Google Scholar 

  26. Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  27. Meguro R, Asano Y, Odagiri S, Li C, Iwatsuki H, Shoumura K (2007) Nonheme-iron histochemistry for light and electron microscopy: a historical, theoretical and technical review. Arch Histol Cytol 70:1–19

    Article  CAS  PubMed  Google Scholar 

  28. Seo JH, Haam YG, Park SW, Kim DW, Jeon GS, Lee C, Hwang DH, Kim YS, Cho SS (2001) Oligodendroglia in the avian retina: immunocytochemical demonstration in the adult bird. J Neurosci Res 65:173–183

    Article  CAS  PubMed  Google Scholar 

  29. Kim J-H, Jeong EM, Jeong Y-J, Lee WJ, Kang JS, Kim I-G, Hwang Y-i (2012) Transglutaminase 2 modulates antigen-specific antibody response by suppressing Blimp-1 and AID expression of B cells in mice. Immunol Lett 147:18–28

    Article  CAS  PubMed  Google Scholar 

  30. Kim MJ, Kim HK, Chung JH, Lim BO, Yamada K, Lim Y, Kang SA (2005) Increased expression of hypothalamic NADPH-diaphorase neurons in mice with iron supplement. Biosci Biotechnol Biochem 69:1978–1981

    Article  CAS  PubMed  Google Scholar 

  31. Negoescu A, Lorimier P, Labat-Moleur F, Drouet C, Robert C, Guillermet C, Brambilla C, Brambilla E (1996) In situ apoptotic cell labeling by the TUNEL method: improvement and evaluation on cell preparations. J Histochem Cytochem 44:959–968

    Article  CAS  PubMed  Google Scholar 

  32. Tokunaga A, Ono K, Ono T, Ogawa M (1992) Magnocellular neurosecretory neurons with ferritin-like immunoreactivity in the hypothalamic supraoptic and paraventricular nuclei of the rat. Brain Res 597:170–175

    Article  CAS  PubMed  Google Scholar 

  33. Hansen TM, Nielsen H, Bernth N, Moos T (1999) Expression of ferritin protein and subunit mRNAs in normal and iron deficient rat brain. Mol Brain Res 65:186–197

    Article  CAS  PubMed  Google Scholar 

  34. Reif DW (1992) Ferritin as a source of iron for oxidative damage. Free Radic Biol Med 12:417–427

    Article  CAS  PubMed  Google Scholar 

  35. Ray PD, Huang B-W, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Giorgi C, Agnoletto C, Baldini C, Bononi A, Bonora M, Marchi S, Missiroli S, Patergnani S, Poletti F, Rimessi A (2010) Redox control of protein kinase C: cell-and disease-specific aspects. Antioxidants redox signaling 13:1051–1085

    Article  CAS  PubMed  Google Scholar 

  37. Yoshida M (2008) Gene regulation system of vasopressin and corticotoropin-releasing hormone. Gene Regul Syst Bio 2:GRSB. S424

    Google Scholar 

  38. Storici P, De Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, Silverman RB, Schirmer T (2004) Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5′-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin. J Biol Chem 279:363–373

    Article  CAS  PubMed  Google Scholar 

  39. Vega C, Moreno-Carranza B, Zamorano M, Quintanar-Stephano A, Mendez I, Thebault S, Martinez de la Escalera G, Clapp C (2010) Prolactin promotes oxytocin and vasopressin release by activating neuronal nitric oxide synthase in the supraoptic and paraventricular nuclei. Am J Physiol Regul Integr Comp Physiol 299:R1701–R1708

    Article  CAS  PubMed  Google Scholar 

  40. Yamova L, Atochin D, Glazova M, Chernigovskaya E, Huang P (2007) Role of neuronal nitric oxide in the regulation of vasopressin expression and release in response to inhibition of catecholamine synthesis and dehydration. Neurosci Lett 426:160–165

    Article  CAS  PubMed  Google Scholar 

  41. Gillard ER, Coburn CG, de Leon A, Snissarenko EP, Bauce LG, Pittman QJ, Hou B, Curras-Collazo MC (2007) Vasopressin autoreceptors and nitric oxide-dependent glutamate release are required for somatodendritic vasopressin release from rat magnocellular neuroendocrine cells responding to osmotic stimuli. Endocrinology 148:479–489

    Article  CAS  PubMed  Google Scholar 

  42. Bharath S, Hsu M, Kaur D, Rajagopalan S, Andersen JK (2002) Glutathione, iron and parkinson’s disease. Biochem Pharmacol 64:1037–1048

    Article  CAS  PubMed  Google Scholar 

  43. Altamura S, Muckenthaler MU (2009) Iron toxicity in diseases of aging: alzheimer’s disease, parkinson’s disease and atherosclerosis. J Alzheimers Dis 16:879–895

    Article  CAS  PubMed  Google Scholar 

  44. Connor JR, Pavlick G, Karli D, Menzies SL, Palmer C (1995) A histochemical study of iron-positive cells in the developing rat brain. J Comp Neurol 355:111–123

    Article  CAS  PubMed  Google Scholar 

  45. Sturrock RR (1992) Stability of neuron number in the ageing mouse paraventricular nucleus. Ann Anat 174:337–340

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2011095), and the intramural research grant of Chungbuk National University in 2015.

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  1. Jong-A Hyeun

    Present address: Department of Biochemistry, Chungbuk National University College of Medicine, Cheongju, Chungbuk, 28644, Republic of Korea

Authors and Affiliations

  1. Department of Anatomy, Chungbuk National University College of Medicine, Chungdae-ro 1, Seowon-gu, Cheongju, Chungbuk, 28644, Republic of Korea

    Jong-A Hyeun, Ji Young Kim, Eun Young Lee & Je Hoon Seo

  2. Department of Pharmacology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, 28644, Republic of Korea

    Chan Hyung Kim

  3. Department of Biomedical Laboratory Science, College of Health Science, Cheongju University, Cheongju, Chungbuk, 28503, Republic of Korea

    Jin-Hee Kim

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Hyeun, JA., Kim, J.Y., Kim, C.H. et al. Iron is Responsible for Production of Reactive Oxygen Species Regulating Vasopressin Expression in the Mouse Paraventricular Nucleus. Neurochem Res 44, 1201–1213 (2019). https://doi.org/10.1007/s11064-019-02764-x

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