Skip to main content

Advertisement

SpringerLink
Log in

NF-κB Blockade in Hypothalamic Paraventricular Nucleus Inhibits High-Salt-Induced Hypertension Through NLRP3 and Caspase-1

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

High-salt-induced inflammation and oxidative stress in the hypothalamic paraventricular nucleus (PVN) contribute to the pathogenesis of salt-sensitive hypertension. In this study, we hypothesized that chronic inhibition of nuclear factor-κB (NF-κB) activity in the PVN delays the progression of hypertension by upregulating anti-inflammatory cytokines, reducing NLRP3 (NOD-like receptor family pyrin domain containing 3) and IL-1β and attenuating p-IKKβ, NF-κB p65 activity and NAD(P)H oxidase in the PVN of salt-sensitive hypertensive rats. Dahl salt-sensitive rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks and were treated with bilateral PVN infusion with either vehicle or pyrrolidine dithiocarbamate (PDTC, 5 μg/h), a NF-κB inhibitor via osmotic minipump. The mean arterial pressure and plasma levels of norepinephrine (NE) and epinephrine (EPI) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of p-IKKβ, NF-κB p65 activity, Fra-like (Fra-LI) activity (an indicator of chronic neuronal activation), NOX-4 (subunits of NAD(P)H oxidase), NLRP3 and IL-1β, and lower levels of IL-10 in the PVN than normal diet rats. Bilateral PVN infusions of PDTC attenuated these high-salt-induced changes. These findings suggest that high-salt-induced NF-κB activation in the PVN caused hypertension via sympathoexcitation, which are associated with the increases of NLRP3, IL-1β and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates NLRP3, IL-1β and oxidative stress in the PVN and thereby attenuates hypertension.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Li, N., Luo, W., Juhong, Z., Yang, J., Wang, H., Zhou, L., & Chang, J. (2010). Associations between genetic variations in the FURIN gene and hypertension. BMC Medical Genetics, 11, 124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dornas, W. C., & Silva, M. E. (2011). Animal models for the study of arterial hypertension. Journal of Biosciences, 36, 731–737.

    Article  PubMed  Google Scholar 

  3. Zhang, M., Qin, D. N., Suo, Y. P., Su, Q., Li, H. B., Miao, Y. W., et al. (2015). Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension. Toxicology Letters, 235, 206–215.

    Article  CAS  PubMed  Google Scholar 

  4. Huang, B. S., Zheng, H., Tan, J., Patel, K. P., & Leenen, F. H. (2011). Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone. Experimental Physiology, 96, 1028–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Qi, J., Zhang, D. M., Suo, Y. P., Song, X. A., Yu, X. J., Elks, C., et al. (2013). Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovascular Toxicology, 13, 48–54.

    Article  CAS  PubMed  Google Scholar 

  6. Li, H. B., Qin, D. N., Ma, L., Miao, Y. W., Zhang, D. M., Lu, Y., et al. (2014). Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension. Toxicology and Applied Pharmacology, 279, 141–149.

    Article  CAS  PubMed  Google Scholar 

  7. Kang, Y. M., Ma, Y., Zheng, J. P., Elks, C., Sriramula, S., Yang, Z. M., & Francis, J. (2009). Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovascular Research, 82, 503–512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dinarello, C. A. (2009). Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology, 27, 519–550.

    Article  CAS  PubMed  Google Scholar 

  9. Mohamed, I. N., Hafez, S. S., Fairaq, A., Ergul, A., Imig, J. D., & El-Remessy, A. B. (2014). Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia, 57, 413–423.

    Article  CAS  PubMed  Google Scholar 

  10. Yu, X. J., Zhang, D. M., Jia, L. L., Qi, J., Song, X. A., Tan, H., et al. (2015). Inhibition of NF-kappaB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress. Toxicology and Applied Pharmacology, 284, 315–322.

    Article  CAS  PubMed  Google Scholar 

  11. Bauernfeind, F. G., Horvath, G., Stutz, A., Alnemri, E. S., MacDonald, K., Speert, D., et al. (2009). Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. Journal of Immunology, 183, 787–791.

    Article  CAS  Google Scholar 

  12. Cao, Y., Mu, J. J., Fang, Y., Yuan, Z. Y., & Liu, F. Q. (2013). Impact of high salt independent of blood pressure on PRMT/ADMA/DDAH pathway in the aorta of dahl salt-sensitive rats. International Journal of Molecular Sciences, 14, 8062–8072.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kang, Y. M., Ma, Y., Elks, C., Zheng, J. P., Yang, Z. M., & Francis, J. (2008). Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: Role of nuclear factor-kappaB. Cardiovascular Research, 79, 671–678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu, X. J., Suo, Y. P., Qi, J., Yang, Q., Li, H. H., Zhang, D. M., et al. (2013). Interaction between AT1 receptor and NF-kappaB in hypothalamic paraventricular nucleus contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure. Cardiovascular Toxicology, 13, 381–390.

    Article  CAS  PubMed  Google Scholar 

  15. Wei, S. G., Yu, Y., Zhang, Z. H., Weiss, R. M., & Felder, R. B. (2008). Mitogen-activated protein kinases mediate upregulation of hypothalamic angiotensin II type 1 receptors in heart failure rats. Hypertension, 52, 679–686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Okada, S., Yamaguchi-Shima, N., Shimizu, T., Arai, J., Yorimitsu, M., & Yokotani, K. (2008). Brain nuclear factor kappa B is involved in the corticotropin-releasing factor-induced central activation of sympatho-adrenomedullary outflow in rats. European Journal of Pharmacology, 584, 207–212.

    Article  CAS  PubMed  Google Scholar 

  17. Kang, Y. M., Gao, F., Li, H. H., Cardinale, J. P., Elks, C., Zang, W. J., et al. (2011). NF-kappaB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure. Basic Research in Cardiology, 106, 1087–1097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Francis, J., MohanKumar, S. M., & MohanKumar, P. S. (2000). Correlations of norepinephrine release in the paraventricular nucleus with plasma corticosterone and leptin after systemic lipopolysaccharide: Blockade by soluble IL-1 receptor. Brain Research, 867, 180–187.

    Article  CAS  PubMed  Google Scholar 

  19. Yi, Q. Y., Qi, J., Yu, X. J., Li, H. B., Zhang, Y., Su, Q., et al. (2015). Paraventricular nucleus infusion of epigallocatechin-3-O-gallate improves renovascular hypertension. Cardiovascular Toxicology. doi:10.1007/s12012-015-9335-x.

    PubMed  Google Scholar 

  20. Kang, Y. M., Zhang, A. Q., Zhao, X. F., Cardinale, J. P., Elks, C., Cao, X. M., et al. (2011). Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure. Basic Research in Cardiology, 106, 473–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, A. D., Zhang, S. J., Yuan, N., Xu, Y., De, W., Gao, X. Y., & Zhu, G. Q. (2011). Angiotensin AT1 receptors in paraventricular nucleus contribute to sympathetic activation and enhanced cardiac sympathetic afferent reflex in renovascular hypertensive rats. Experimental Physiology, 96, 94–103.

    Article  CAS  PubMed  Google Scholar 

  22. Zhu, G. Q., Gao, L., Patel, K. P., Zucker, I. H., & Wang, W. (2004). ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure. Journal of Applied Physiology, 97, 1746–1754.

    Article  CAS  PubMed  Google Scholar 

  23. Li, H. B., Qin, D. N., Cheng, K., Su, Q., Miao, Y. W., Guo, J., et al. (2015). Central blockade of salusin beta attenuates hypertension and hypothalamic inflammation in spontaneously hypertensive rats. Scientific Reports, 5, 11162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Su, Q., Qin, D. N., Wang, F. X., Ren, J., Li, H. B., Zhang, M., et al. (2014). Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicology and Applied Pharmacology, 276, 115–120.

    Article  CAS  PubMed  Google Scholar 

  25. Kang, Y. M., He, R. L., Yang, L. M., Qin, D. N., Guggilam, A., Elks, C., et al. (2009). Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovascular Research, 83, 737–746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. MohanKumar, S. M., MohanKumar, P. S., & Quadri, S. K. (1998). Specificity of interleukin-1beta-induced changes in monoamine concentrations in hypothalamic nuclei: Blockade by interleukin-1 receptor antagonist. Brain Research Bulletin, 47, 29–34.

    Article  CAS  PubMed  Google Scholar 

  27. Kang, Y. M., Zhang, Z. H., Johnson, R. F., Yu, Y., Beltz, T., Johnson, A. K., et al. (2006). Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circulation Research, 99, 758–766.

    Article  CAS  PubMed  Google Scholar 

  28. Sriramula, S., Cardinale, J. P., Lazartigues, E., & Francis, J. (2011). ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension. Cardiovascular Research, 92, 401–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Miller, F. J, Jr, Gutterman, D. D., Rios, C. D., Heistad, D. D., & Davidson, B. L. (1998). Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circulation Research, 82, 1298–1305.

    Article  CAS  PubMed  Google Scholar 

  30. Li, Z. W., Chu, W., Hu, Y., Delhase, M., Deerinck, T., Ellisman, M., et al. (1999). The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. The Journal of Experimental Medicine, 189, 1839–1845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wei, J., & Liang, B. S. (2012). PPM1B and P-IKKbeta expression levels correlated inversely with rat gastrocnemius atrophy after denervation. Brazilian Journal of Medical and Biological Research, 45, 711–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sandanger, O., Ranheim, T., Vinge, L. E., Bliksoen, M., Alfsnes, K., Finsen, A. V., et al. (2013). The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovascular Research, 99, 164–174.

    Article  CAS  PubMed  Google Scholar 

  33. Tschopp, J., Martinon, F., & Burns, K. (2003). NALPs: A novel protein family involved in inflammation. Nature Reviews Molecular Cell Biology, 4, 95–104.

    Article  CAS  PubMed  Google Scholar 

  34. Bronner, D. N., Abuaita, B. H., Chen, X., Fitzgerald, K. A., Nunez, G., He, Y., et al. (2015). Endoplasmic reticulum stress activates the inflammasome via NLRP3-and caspase-2-driven mitochondrial damage. Immunity, 43, 451–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kim, S., Joe, Y., Jeong, S. O., Zheng, M., Back, S. H., Park, S. W., et al. (2014). Endoplasmic reticulum stress is sufficient for the induction of IL-1beta production via activation of the NF-kappaB and inflammasome pathways. Innate immunity, 20, 799–815.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by National Basic Research Program of China (No. 2012CB517805) and National Natural Science Foundation of China (Nos. 91439120, 81370356, 81170248, 81471471). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an Jiaotong University Cardiovascular Research Center, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Jie Qi, Xiao-Jing Yu, Hong-Li Gao, Qiu-Yue Yi, Hong Tan, Xiao-Yan Fan, Yan Zhang, Xin-Ai Song, Jin-Jun Liu & Yu-Ming Kang

  2. Department of Pharmacology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Xiao-Lian Shi

  3. Department of Pathology, Xi’an Jiaotong University School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Hong Tan

  4. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Wei Cui

Authors
  1. Jie Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Jing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Lian Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Li Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiu-Yue Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Yan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xin-Ai Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jin-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yu-Ming Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Ming Kang.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, J., Yu, XJ., Shi, XL. et al. NF-κB Blockade in Hypothalamic Paraventricular Nucleus Inhibits High-Salt-Induced Hypertension Through NLRP3 and Caspase-1. Cardiovasc Toxicol 16, 345–354 (2016). https://doi.org/10.1007/s12012-015-9344-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-015-9344-9

Keywords

Search

Navigation