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Assessing the role of hypothalamic microglia and blood vessel disruption in the development of angiotensin II-dependent hypertension in Cyp1a1-Ren2 rats

  • Aaron K. Korpal
  • Colin H. Brown
  • Daryl O. SchwenkeEmail author
Integrative Physiology
Part of the following topical collections:
  1. Integrative Physiology

Abstract

Elevated plasma levels of the hormone vasopressin have been implicated in the pathogenesis of some forms of hypertension. Hypothalamic paraventricular and supraoptic nuclei neurons regulate vasopressin secretion into the circulation. Vasopressin neuron activity is elevated by day 7 in the development of angiotensin II-dependent hypertension in Cyp1a1-Ren2 rats. While microglial activation and blood-brain barrier (BBB) breakdown contribute to the maintenance of well-established hypertension, it is not known whether these mechanisms contribute to the early onset of hypertension. Hence, we aimed to determine whether microglia are activated and/or the BBB is compromised during the onset of hypertension. Here, we used the Cyp1a1-Ren2 rat model of hypertension and showed that ionised calcium-binding adapter molecule 1 staining of microglia does not change in the paraventricular and supraoptic nuclei on day 7 (early onset) and day 28 (well established) of hypertension, compared to the normotensive control. Endothelial transferrin receptor staining, which stains endothelia and reflects blood vessel density, was also unchanged at day 7, but was reduced at day 28, suggesting that breakdown of the BBB begins between day 7 and day 28 in the development of hypertension. Hence, this study does not support the idea that microglial activation or BBB disruption contribute to the onset of angiotensin II-dependent hypertension in Cyp1a1-Ren2 rats, although BBB disruption might contribute to the progression from the early onset to well-established hypertension.

Keywords

Vasopressin Oxytocin Microglia Blood-brain barrier Angiotensin II Hypertension 

Notes

Acknowledgements

The authors are grateful to Prof John Mullins (University of Edinburgh) for the gift of Cyp1a1-Ren2 rats to find the colony used in this manuscript.

Author contributions

AKK performed all experiments, analysed results, contributed to the interpretation of data and wrote the first draft of manuscript. CHB and DOS conceived, designed and supervised the study, interpreted data and wrote subsequent drafts of the manuscript.

Funding

This work was supported by a Project Support Grant from the British Society for Neuroendocrinology and a University of Otago PhD Scholarship.

Compliance with ethical standards

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. 1.
    Bakris G, Bursztyn M, Gavras I, Bresnahan M, Gavras H (1997) Role of vasopressin in essential hypertension: racial differences. J Hypertens 15:545–550CrossRefPubMedGoogle Scholar
  2. 2.
    Bartfai T, Schultzberg M (1993) Cytokines in neuronal cell types. Neurochem Int 22:435–444CrossRefPubMedGoogle Scholar
  3. 3.
    Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE (2014) Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension 63:572–579CrossRefPubMedGoogle Scholar
  4. 4.
    Brown CH (2016) Magnocellular neurons and posterior pituitary function. Compr Physiol 6:1701–1741CrossRefPubMedGoogle Scholar
  5. 5.
    Brown CH, Ruan M, Scott V, Tobin VA, Ludwig M (2008) Multi-factorial somato-dendritic regulation of phasic spike discharge in vasopressin neurons. Prog Brain Res 170:219–228CrossRefPubMedGoogle Scholar
  6. 6.
    Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, Kidd GJ, Bergmann CC, Stohlman SA, Trapp BD (2012) Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci 32:11706–11715CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chockalingam A, Campbell NR, Fodor JG (2006) Worldwide epidemic of hypertension. Can J Cardiol 22:553–555CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Choe KY, Han SY, Gaub P, Shell B, Voisin DL, Knapp BA, Barker PA, Brown CH, Cunningham JT, Bourque CW (2015) High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons. Neuron 85:549–560CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Choi SS, Lee HJ, Lim I, Satoh J, Kim SU (2014) Human astrocytes: secretome profiles of cytokines and chemokines. PLoS One 9:e92325CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dampney RA, Horiuchi J, Killinger S, Sheriff MJ, Tan PS, McDowall LM (2005) Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. Clin Exp Pharmacol Physiol 32:419–425CrossRefPubMedGoogle Scholar
  11. 11.
    de Paula RB, Plavnik FL, Rodrigues CI, Neves Fde A, Kohlmann O Jr, Ribeiro AB, Gavras I, Gavras H (1993) Contribution of vasopressin to orthostatic blood pressure maintenance in essential hypertension. Am J Hypertens 6:794–798CrossRefPubMedGoogle Scholar
  12. 12.
    Ferri CC, Ferguson AV (2003) Interleukin-1 beta depolarizes paraventricular nucleus parvocellular neurones. J Neuroendocrinol 15:126–133CrossRefPubMedGoogle Scholar
  13. 13.
    Fleegal-DeMotta MA, Doghu S, Banks WA (2009) Angiotensin II modulates BBB permeability via activation of the AT(1) receptor in brain endothelial cells. J Cereb Blood Flow Metab 29:640–647CrossRefPubMedGoogle Scholar
  14. 14.
    Freidin M, Bennett MV, Kessler JA (1992) Cultured sympathetic neurons synthesize and release the cytokine interleukin 1 beta. Proc Natl Acad Sci U S A 89:10440–10443CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7:335–346CrossRefPubMedGoogle Scholar
  16. 16.
    Han SY, Bouwer GT, Seymour AJ, Korpal AK, Schwenke DO, Brown CH (2015) Induction of hypertension blunts baroreflex inhibition of vasopressin neurons in the rat. Eur J Neurosci 42:2690–2698CrossRefPubMedGoogle Scholar
  17. 17.
    Han SY, Gray E, Hughes G, Brown CH, Schwenke DO (2014) Increased sympathetic drive during the onset of hypertension in conscious Cyp1a1-Ren2 rats. Pflugers Arch 466:459–466CrossRefPubMedGoogle Scholar
  18. 18.
    Hasser EM, Bishop VS, Hay M (1997) Interactions between vasopressin and baroreflex control of the sympathetic nervous system. Clin Exp Pharmacol Physiol 24:102–108CrossRefPubMedGoogle Scholar
  19. 19.
    Hofman P, Hoyng P, vanderWerf F, Vrensen GF, Schlingemann RO (2001) Lack of blood-brain barrier properties in microvessels of the prelaminar optic nerve head. Invest Ophthalmol Vis Sci 42:895–901PubMedGoogle Scholar
  20. 20.
    Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KC, Mason DY (1984) Transferrin receptor on endothelium of brain capillaries. Nature 312:162–163CrossRefPubMedGoogle Scholar
  21. 21.
    Kantachuvesiri S, Fleming S, Peters J, Peters B, Brooker G, Lammie AG, McGrath I, Kotelevtsev Y, Mullins JJ (2001) Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem 276:36727–36733CrossRefPubMedGoogle Scholar
  22. 22.
    Korpal AK, Han SY, Schwenke DO, Brown CH (2018) A switch from GABA inhibition to excitation of vasopressin neurones exacerbates the development of angiotensin II-dependent hypertension. J Neuroendocrinol In PressGoogle Scholar
  23. 23.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, DK MG, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2016) Heart Disease and Stroke Statistics—2016 Update: a report from the American Heart Association. Circulation 133:e38–360CrossRefPubMedGoogle Scholar
  24. 24.
    Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates, 6th edn. Elsevier, Amsterdam NetherlandsGoogle Scholar
  25. 25.
    Shen XZ, Li Y, Li L, Shah KH, Bernstein KE, Lyden P, Shi P (2015) Microglia participate in neurogenic regulation of hypertension. Hypertension 66:309–316CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shi P, Diez-Freire C, Jun JY, Qi Y, Katovich MJ, Li Q, Sriramula S, Francis J, Sumners C, Raizada MK (2010) Brain microglial cytokines in neurogenic hypertension. Hypertension 56:297–303CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Simmons DM, Swanson LW (2009) Comparison of the spatial distribution of seven types of neuroendocrine neurons in the rat paraventricular nucleus: toward a global 3D model. J Comp Neurol 516:423–441CrossRefPubMedGoogle Scholar
  28. 28.
    Smith PA, Graham LN, Mackintosh AF, Stoker JB, Mary DA (2004) Relationship between central sympathetic activity and stages of human hypertension. Am J Hypertens 17:217–222CrossRefPubMedGoogle Scholar
  29. 29.
    Smith PM, Ferguson AV (1997) Vasopressin acts in the subfornical organ to decrease blood pressure. Neuroendocrinology 66:130–135CrossRefPubMedGoogle Scholar
  30. 30.
    Son SJ, Filosa JA, Potapenko ES, Biancardi VC, Zheng H, Patel KP, Tobin VA, Ludwig M, Stern JE (2013) Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron 78:1036–1049CrossRefPubMedGoogle Scholar
  31. 31.
    Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ, Stohlman S, Ransohoff R (2007) Evidence for synaptic stripping by cortical microglia. Glia 55:360–368CrossRefPubMedGoogle Scholar
  32. 32.
    Yang CR, Phillips MI, Renaud LP (1992) Angiotensin II receptor activation depolarizes rat supraoptic neurons in vitro. Am J Phys 263:R1333–R1338Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Brain Health Research CentreUniversity of OtagoDunedinNew Zealand
  2. 2.Centre for NeuroendocrinologyUniversity of OtagoDunedinNew Zealand
  3. 3.HeartOtagoUniversity of OtagoDunedinNew Zealand
  4. 4.Department of PhysiologyUniversity of OtagoDunedinNew Zealand

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