Restraint stress-induced expression of Fos and several related genes in the hypothalamus of the hypertensive ISIAH rats

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Abstract

Stress can play a significant role in the development of arterial hypertension and many other complications of cardiovascular diseases. Considerable attention is paid to the study of the molecular mechanisms involved in the body’s response to stressful influences, but there are still many blank spots in understanding the details. ISIAH rats model a stress-sensitive form of arterial hypertension. ISIAH rats are characterized by genetically determined enhanced hypothalamic-adrenal-cortical and sympathetic adrenomedullary systems activity, which suggests a functional state of increased stress reactivity. In the present study, for the first time, the time course of the Fos and several related genes’ expression was studied in the hypothalamus of adult male hypertensive ISIAH rats after exposure to a single restraint stress of different duration (30, 60, and 120 minutes). The results of the study showed the activation of Fos transcription with a peak 1 hour after the onset of restraint stress. The dynamics of Fos gene activation coincides with the dynamics of blood pressure increase after stress. Restraint stress also alters the transcription of several other genes encoding transcription factors (Jun, Nr4a3, Jdp2, Ppargc1a) associated with the development of cardiovascular diseases. Since Fos induction is a marker of brain neuron activation, we can conclude that increased stress reactivity of the hypothalamic-pituitary-adrenocortical and sympathoadrenal systems of hypertensive ISIAH rats during short-term restriction is accompanied by activation of hypothalamic neurons and increased blood pressure level.

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About the authors

Yu. V. Makovka

Federal Research Center, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences; Novosibirsk State University

Author for correspondence.
Email: makovkayv@bionet.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090

L. A. Fedoseeva

Federal Research Center, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Email: makovkayv@bionet.nsc.ru
Russian Federation, Novosibirsk, 630090

D. Yu. Oshchepkov

Federal Research Center, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Email: makovkayv@bionet.nsc.ru
Russian Federation, Novosibirsk, 630090

A. L. Markel

Federal Research Center, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences; Novosibirsk State University

Email: makovkayv@bionet.nsc.ru
Russian Federation, Novosibirsk, 630090; Novosibirsk, 630090

O. E. Redina

Federal Research Center, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Email: makovkayv@bionet.nsc.ru
Russian Federation, Novosibirsk, 630090

References

  1. Markel A.L. (1992) Development of a new strain of rats with inherited stress-induced arterial hypertension. Genetic Hypertension. 218, 405–407.
  2. Markel A.L., Maslova L.N., Shishkina G.T., Bulygina V.V., Machanova N.A., Jacobson G.S. (1999) Developmental influences on blood pressure regulation in ISIAH rats. Dev. Нypertensive Phenotype: Basic and Clin. Studies. 19, 493–526.
  3. Markel A.L., Redina O.E., Gilinsky M.A., Dymshits G.M., Kalashnikova E.V., Khvorostova Y.V., Fedoseeva L.A., Jacobson G.S. (2007) Neuroendocrine profiling in inherited stress-induced arterial hypertension rat strain with stress-sensitive arterial hypertension. J. Endocrinol. 195, 439–450.
  4. Redina O.E., Smolenskaya S.E., Polityko Y.K., Ershov N.I., Gilinsky M.A., Markel A.L. (2021). Hypothalamic norepinephrine concentration and heart mass in hypertensive ISIAH rats are associated with a genetic locus on chromosome 18. J. Pers. Med. 11(2), 67.
  5. Klimov L.O., Ershov N.I., Efimov V.M., Markel A.L., Redina O.E. (2016) Genome-wide transcriptome analysis of hypothalamus in rats with inherited stress-induced arterial hypertension. BMC Genet. 17(Suppl 1), 13.
  6. Fedoseeva L.A., Klimov L.O., Ershov N.I., Alexandrovich Y.V., Efimov V.M., Markel A.L., Redina O.E. (2016) Molecular determinants of the adrenal gland functioning related to stress-sensitive hypertension in ISIAH rats. BMC Genomics. 17(Suppl 14), 989.
  7. Fedoseeva L.A., Ryazanova M.A., Ershov N.I., Markel A.L., Redina O.E. (2016) Comparative transcriptional profiling of renal cortex in rats with inherited stress-induced arterial hypertension and normotensive Wistar Albino Glaxo rats. BMC Genet. 17(Suppl 1), 12.
  8. Ryazanova M.A., Fedoseeva L.A., Ershov N.I., Efimov V.M., Markel A.L., Redina O.E. (2016) The gene-expression profile of renal medulla in ISIAH rats with inherited stress-induced arterial hypertension. BMC Genet. 17(Suppl 3), 151.
  9. Fedoseeva L.A., Klimov L.O., Ershov N.I., Efimov V.M., Markel A.L., Orlov Y.L., Redina O.E. (2019) The differences in brain stem transcriptional profiling in hypertensive ISIAH and normotensive WAG rats. BMC Genomics. 20, 297.
  10. Пыльник Т.О., Плетнева Л.С., Редина О.Е., Смоленская С.Э., Маркель А.Л., Иванова Л.Н. (2011) Влияние эмоционального стресса на экспрессию мРНК гена α-ENaC в почке гипертензивных крыс линии НИСАГ. Докл. Акад. Наук. 439(4), 563–565.
  11. Абрамова Т.О., Редина О.Е., Смоленская Ю.П., Маркель А. (2013) Усиленная экспрессия гена EPHX2 в почках гипертензивных крыс НИСАГ. Молекуляр. биология. 47(6), 942–948.
  12. Абрамова Т.О., Смоленская С.Э., Антонов E.В., Редина О.Е., Маркель А.Л. (2016) Экспрессия генов катехол-о-метилтрансферазы (COMT), минералокортикоидного рецептора (MLR) и эпителиального натриевого канала (ENAC) в почках гипертензивных крыс линии НИСАГ (ISIAH) в покое и при ответе на стресс. Генетика. 52(2), 180–187.
  13. Senba E., Ueyama T. (1997) Stress-induced expression of immediate early genes in the brain and peripheral organs of the rat. Neurosci. Res. 29, 183–207.
  14. Girotti M., Weinberg M.S., Spencer R.L. (2007) Differential responses of hypothalamus-pituitary-adrenal axis immediate early genes to corticosterone and circadian drive. Endocrinology. 148, 2542–2552.
  15. Mansi J.A., Rivest S., Drolet G. (1998) Effect of immobilization stress on transcriptional activity of inducible immediate-early genes, corticotropin-releasing factor, its type 1 receptor, and enkephalin in the hypothalamus of borderline hypertensive rats. J. Neurochem. 70, 1556–1566.
  16. Kovacs K.J. (2008) Measurement of immediate-early gene activation – c-fos and beyond. J. Neuroendocrinol. 20, 665–672.
  17. Guez-Barber D., Fanous S., Golden S.A., Schrama R., Koya E., Stern A.L., Bossert J.M., Harvey B.K., Picciotto M.R., Hope B.T. (2011) FACS identifies unique cocaine-induced gene regulation in selectively activated adult striatal neurons. J. Neurosci. 31, 4251–4259.
  18. Okuno H. (2011) Regulation and function of immediate-early genes in the brain: beyond neuronal activity markers. Neurosci. Res. 69, 175–186.
  19. Melia K.R., Ryabinin A.E., Schroeder R., Bloom F.E., Wilson M.C. (1994) Induction and habituation of immediate early gene expression in rat brain by acute and repeated restraint stress. J. Neurosci. 14, 5929–5938.
  20. Girotti M., Pace T.W., Gaylord R.I., Rubin B.A., Herman J.P., Spencer R.L. (2006) Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain. Neuroscience. 138, 1067–1081.
  21. Foletta V.C., Segal D.H., Cohen D.R. (1998) Transcriptional regulation in the immune system: all roads lead to AP-1. J. Leukoc. Biol. 63, 139–152.
  22. Aronheim A., Zandi E., Hennemann H., Elledge S.J., Karin M. (1997) Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions. Mol. Cell. Biol. 17, 3094–3102.
  23. Katz S., Heinrich R., Aronheim A. (2001) The AP-1 repressor, JDP2, is a bona fide substrate for the c-Jun N-terminal kinase. FEBS Lett. 506, 196–200.
  24. Odagiu L., Boulet S., Maurice De Sousa D., Daudelin J.F., Nicolas S., Labrecque N. (2020) Early programming of CD8(+) T cell response by the orphan nuclear receptor NR4A3. Proc. Natl. Acad. Sci. USA. 117, 24392–24402.
  25. Baresic M., Salatino S., Kupr B., van Nimwegen E., Handschin C. (2014) Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1alpha in the regulation of the hypoxic gene program. Mol. Cell. Biol. 34, 2996–3012.
  26. Wenz T. (2013) Regulation of mitochondrial biogenesis and PGC-1alpha under cellular stress. Mitochondrion. 13, 134–142.
  27. McMeekin L.J., Joyce K.L., Jenkins L.M., Bohannon B.M., Patel K.D., Bohannon A.S., Patel A., Fox S.N., Simmons M.S., Day J.J., Kralli A., Crossman D.K., Cowell R.M. (2021) Estrogen-related receptor alpha (ERRalpha) is required for PGC-1alpha-dependent gene expression in the mouse brain. Neuroscience. 479, 70–90.
  28. Hausl A.S., Brix L.M., Hartmann J., Pohlmann M.L., Lopez J.P., Menegaz D., Brivio E., Engelhardt C., Roeh S., Bajaj T., Rudolph L., Stoffel R., Hafner K., Goss H.M., Reul J., Deussing J.M., Eder M., Ressler K.J., Gassen N.C., Chen A., Schmidt M.V. (2021) The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice. Mol. Psychiatry. 26, 3060–3076.
  29. Ginzinger D.G. (2002) Gene quantification using real-time quantitative PCR: an emerging technology hits the mainstream. Exp. Hematol. 30, 503–512.
  30. Imaki T., Shibasaki T., Chikada N., Harada S., Naruse M., Demura H. (1996) Different expression of immediate-early genes in the rat paraventricular nucleus induced by stress: relation to corticotropin-releasing factor gene transcription. Endocr. J. 43, 629–638.
  31. Imaki T., Naruse M., Harada S., Chikada N., Nakajima K., Yoshimoto T., Demura H. (1998) Stress-induced changes of gene expression in the paraventricular nucleus are enhanced in spontaneously hypertensive rats. J. Neuroendocrinol. 10, 635–643.
  32. Budzikowski A.S., Vahid-Ansari F., Leenen F.H. (1998) Chronic activation of brain areas by high-sodium diet in Dahl salt-sensitive rats. Am. J. Physiol. 274, H2046–2052.
  33. Rivest S., Laflamme N. (1995) Neuronal activity and neuropeptide gene transcription in the brains of immune-challenged rats. J. Neuroendocrinol. 7, 501–525.
  34. Cullinan W.E., Herman J.P., Battaglia D.F., Akil H., Watson S.J. (1995) Pattern and time course of immediate early gene expression in rat brain following acute stress. Neuroscience. 64, 477–505.
  35. Crane J.W., French K.R., Buller K.M. (2005) Patterns of neuronal activation in the rat brain and spinal cord in response to increasing durations of restraint stress. Stress. 8, 199–211.
  36. Karin M., Chang L. (2001) AP-1–glucocorticoid receptor crosstalk taken to a higher level. J. Endocrinol. 169, 447–451.
  37. Itoi K., Motoike I., Liu Y., Clokie S., Iwasaki Y., Uchida K., Sato T., Aguilera G. (2019) Genome-wide analysis of glucocorticoid-responsive transcripts in the hypothalamic paraventricular region of male rats. Endocrinology. 160, 38–54.
  38. Kvetnansky R., Sabban E.L., Palkovits M. (2009) Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol. Rev. 89, 535–606.
  39. Daftary S.S., Boudaba C., Tasker J.G. (2000) Noradrenergic regulation of parvocellular neurons in the rat hypothalamic paraventricular nucleus. Neuroscience. 96, 743–751.
  40. Perez D.M. (2020) Alpha(1)-adrenergic receptors in neurotransmission, synaptic plasticity, and cognition. Front. Pharmacol. 11, 581098.
  41. Morris D.P., Lei B., Longo L.D., Bomsztyk K., Schwinn D.A., Michelotti G.A. (2015) Temporal dissection of rate limiting transcriptional events using Pol II ChIP and RNA analysis of adrenergic stress gene activation. PLoS One. 10, e0134442.
  42. Ang S.A., Harrison J.L., Powers-Martin K., Reddrop C., McKitrick D.J., Holobotovskyy V.V., Arnolda L.F., Phillips J.K. (2007) C-Fos activation in renal hypertension. Hypertension. 49, 1468–1468.
  43. Maiti P., Singh S.B., Sharma A.K., Muthuraju S., Banerjee P.K., Ilavazhagan G. (2006) Hypobaric hypoxia induces oxidative stress in rat brain. Neurochem. Int. 49, 709–716.
  44. Zafir A., Banu N. (2009) Induction of oxidative stress by restraint stress and corticosterone treatments in rats. Indian J. Biochem. Biophys. 46, 53–58.
  45. Dal Santo G., Conterato G.M., Barcellos L.J., Rosemberg D.B., Piato A.L. (2014) Acute restraint stress induces an imbalance in the oxidative status of the zebrafish brain. Neurosci. Lett. 558, 103–108.
  46. Liu D., Ma Z., Xu L., Zhang X., Qiao S., Yuan J. (2019) PGC1alpha activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades. Aging (Albany NY). 11, 10061–10073.
  47. Zhao X., Liu F., Jin H., Li R., Wang Y., Zhang W., Wang H., Chen W. (2017) Involvement of PKCalpha and ERK1/2 signaling pathways in EGCG’s protection against stress-induced neural injuries in Wistar rats. Neuroscience. 346, 226–237.
  48. Pang D., Yang C., Luo Q., Li C., Liu W., Li L., Zou Y., Feng B., Chen Z., Huang C. (2020) Soy isoflavones improve the oxidative stress induced hypothalamic inflammation and apoptosis in high fat diet-induced obese male mice through PGC1-alpha pathway. Aging (Albany NY). 12, 8710–8727.
  49. Lucas E.K., Dougherty S.E., McMeekin L.J., Reid C.S., Dobrunz L.E., West A.B., Hablitz J.J., Cowell R.M. (2014) PGC-1alpha provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons. J. Neurosci. 34, 14375–14387.
  50. Lin J., Wu P.H., Tarr P.T., Lindenberg K.S., St-Pierre J., Zhang C.Y., Mootha V.K., Jager S., Vianna C.R., Reznick R.M., Cui L., Manieri M., Donovan M.X., Wu Z., Cooper M.P., Fan M.C., Rohas L.M., Zavacki A.M., Cinti S., Shulman G.I., Lowell B.B., Krainc D., Spiegelman B.M. (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell. 119, 121–135.
  51. Fan W., Evans R. (2015) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr. Opin. Cell. Biol. 33, 49–54.
  52. Zhao Q., Zhang J., Wang H. (2015) PGC-1alpha overexpression suppresses blood pressure elevation in DOCA-salt hypertensive mice. Biosci. Rep. 35, e00217.

Supplementary files

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2. Fig. 1. Dynamics of changes in the content of mRNA genes in comparison with the thalamic ISIAH rat when exposed to restriction stress of different durations.

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3. Fig. 2. The effect of restriction stress of different durations on the level of blood pressure (BP) in male hypertensive ISIAH rats. **p < 0.01; ***p < 0.001 compared with basal blood pressure; #p < 0.05 compared with the blood pressure level in the group of rats after 30 min of restriction stress (Student's t test); &average population level of basal blood pressure (according to [3]).

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4. Fig. 3. Dynamics of stress-induced changes in the mRNA content of early response genes in the hypothalamus of ISIAH rats under the influence of restriction stress of different durations: Fos (a), Jun (b), Nr4a3 (c), Jdp2 (d), Ppargc1a (e), Esrra ( e). *p < 0.05; **p < 0.01 and ***p < 0.001 compared to control, #p < 0.05; ##p < 0.01 compared to the 30-minute stress group; &p < 0.05 compared to 1-hour stress (Post-hoc, LSD test).

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