Skip to main content

Advertisement

SpringerLink
Log in

Intermedin in Paraventricular Nucleus Attenuates Sympathoexcitation and Decreases TLR4-Mediated Sympathetic Activation via Adrenomedullin Receptors in Rats with Obesity-Related Hypertension

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Intermedin/adrenomedullin-2 (IMD/AM2), a member of the calcitonin gene-related peptide/AM family, plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus (PVN) of the hypothalamus on sympathetic nerve activity (SNA), and lipopolysaccharide (LPS)-induced sympathetic activation in obesity-related hypertensive (OH) rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure (MAP) in response to specific drugs. Male rats were fed a control diet (12% kcal as fat) or a high-fat diet (42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4 (TLR4) and plasma norepinephrine (NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS (0.5 µg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD (50 pmol) caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympathetic activation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However, IMD in the PVN decreased the LPS-induced ERK activation, which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover, IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.

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. Hall JE, Crook ED, Jones DW, Wofford MR, Dubbert PM. Mechanisms of obesity-associated cardiovascular and renal disease. Am J Med Sci 2002, 324: 127–137.

    Article  Google Scholar 

  2. Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney disease. Int J Nephrol Renovasc Dis 2014, 7: 75–88.

    Article  Google Scholar 

  3. Head GA, Lim K, Barzel B, Burke SL, Davern PJ. Central nervous system dysfunction in obesity-induced hypertension. Curr Hypertens Rep 2014, 16: 466.

    Article  Google Scholar 

  4. Lu QB, Sun J, Kang Y, Sun HJ, Wang HS, Wang Y, et al. Superoxide anions and NO in the paraventricular nucleus modulate the cardiac sympathetic afferent reflex in obese rats. Int J Mol Sci 2017, 19.

  5. Zhu H, Tan L, Li Y, Li J, Qiu M, Li L, et al. Increased apoptosis in the paraventricular nucleus mediated by AT1R/Ras/ERK1/2 signaling results in sympathetic hyperactivity and renovascular hypertension in rats after kidney injury. Front Physiol 2017, 8: 41.

    PubMed  PubMed Central  Google Scholar 

  6. Bai J, Yu XJ, Liu KL, Wang FF, Jing GX, Li HB, et al. Central administration of tert-butylhydroquinone attenuates hypertension via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus of hypertensive rats. Toxicol Appl Pharmacol 2017, 333: 100–109.

    Article  CAS  Google Scholar 

  7. de Kloet AD, Pioquinto DJ, Nguyen D, Wang L, Smith JA, Hiller H, et al. Obesity induces neuroinflammation mediated by altered expression of the renin-angiotensin system in mouse forebrain nuclei. Physiol Behav 2014, 136: 31–38.

    Article  Google Scholar 

  8. Xue B, Yu Y, Zhang Z, Guo F, Beltz TG, Thunhorst RL, et al. Leptin mediates high-fat diet sensitization of angiotensin II-elicited hypertension by upregulating the brain renin-angiotensin system and inflammation. Hypertension 2016, 67: 970–976.

    Article  CAS  Google Scholar 

  9. Huang X, Wang Y, Ren K. Deleterious effect of salusin-beta in paraventricular nucleus on sympathetic activity and blood pressure via NF-kappaB signaling in a rat model of obesity hypertension. Pharmazie 2015, 70: 543–548.

    CAS  PubMed  Google Scholar 

  10. Chen F, Cham JL, Badoer E. High-fat feeding alters the cardiovascular role of the hypothalamic paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 2010, 298: R799–807.

    Article  CAS  Google Scholar 

  11. Dange RB, Agarwal D, Teruyama R, Francis J. Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension. J Neuroinflammation 2015, 12: 31.

    Article  Google Scholar 

  12. Biancardi VC, Stranahan AM, Krause EG, de Kloet AD, Stern JE. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. Am J Physiol Heart Circ Physiol 2016, 310: H404–415.

    Article  Google Scholar 

  13. Li HB, Li X, Huo CJ, Su Q, Guo J, Yuan ZY, et al. TLR4/MyD88/NF-kappaB signaling and PPAR-gamma within the paraventricular nucleus are involved in the effects of telmisartan in hypertension. Toxicol Appl Pharmacol 2016, 305: 93–102.

    Article  CAS  Google Scholar 

  14. Paladino N, Leone MJ, Plano SA, Golombek DA. Paying the circadian toll: the circadian response to LPS injection is dependent on the Toll-like receptor 4. J Neuroimmunol 2010, 225: 62–67.

    Article  CAS  Google Scholar 

  15. Roh J, Chang CL, Bhalla A, Klein C, Hsu SY. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem 2004, 279: 7264–7274.

    Article  CAS  Google Scholar 

  16. Takei Y, Hashimoto H, Inoue K, Osaki T, Yoshizawa-Kumagaye K, Tsunemi M, et al. Central and peripheral cardiovascular actions of adrenomedullin 5, a novel member of the calcitonin gene-related peptide family, in mammals. J Endocrinol 2008, 197: 391–400.

    Article  CAS  Google Scholar 

  17. Takei Y, Inoue K, Ogoshi M, Kawahara T, Bannai H, Miyano S. Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator. FEBS Lett 2004, 556: 53–58.

    Article  CAS  Google Scholar 

  18. Xiong XQ, Chen WW, Han Y, Zhou YB, Zhang F, Gao XY, et al. Enhanced adipose afferent reflex contributes to sympathetic activation in diet-induced obesity hypertension. Hypertension 2012, 60: 1280–1286.

    Article  CAS  Google Scholar 

  19. Oliver KR, Kane SA, Salvatore CA, Mallee JJ, Kinsey AM, Koblan KS, et al. Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat. Eur J Neurosci 2001, 14: 618–628.

    Article  CAS  Google Scholar 

  20. Stachniak TJ, Krukoff TL. Receptor activity modifying protein 2 distribution in the rat central nervous system and regulation by changes in blood pressure. J Neuroendocrinol 2003, 15: 840–850.

    Article  CAS  Google Scholar 

  21. Hashimoto H, Kitamura K, Kawasaki M, Saito T, Suzuki H, Otsubo H, et al. Adrenomedullin 2/intermedin-like immunoreactivity in the hypothalamus and brainstem of rats. Auton Neurosci 2008, 139: 46–54.

    Article  CAS  Google Scholar 

  22. Zhang JS, Hou YL, Lu WW, Ni XQ, Lin F, Yu YR, et al. Intermedin1-53 protects against myocardial fibrosis by inhibiting endoplasmic reticulum stress and inflammation induced by homocysteine in apolipoprotein E-deficient mice. J Atheroscler Thromb 2016, 23: 1294–1306.

    Article  CAS  Google Scholar 

  23. Pang Y, Li Y, Lv Y, Sun L, Zhang S, Li Y, et al. Intermedin restores hyperhomocysteinemia-induced macrophage polarization and improves insulin resistance in mice. J Biol Chem 2016, 291: 12336–12345.

    Article  CAS  Google Scholar 

  24. Wang Y, Tian J, Guo H, Mi Y, Zhang R, Li R. Intermedin ameliorates IgA nephropathy by inhibition of oxidative stress and inflammation. Clin Exp Med 2016, 16: 183–192.

    Article  CAS  Google Scholar 

  25. Zhou YB, Sun HJ, Chen D, Liu TY, Han Y, Wang JJ, et al. Intermedin in paraventricular nucleus attenuates sympathetic activity and blood pressure via nitric oxide in hypertensive rats. Hypertension 2014, 63: 330–337.

    Article  CAS  Google Scholar 

  26. Zhang ZH, Yu Y, Wei SG, Felder RB. Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling. J Hypertens 2010, 28: 806–816.

    Article  CAS  Google Scholar 

  27. Carnagarin R, Matthews V, Gregory C, Schlaich MP. Pharmacotherapeutic strategies for treating hypertension in patients with obesity. Expert Opin Pharmacother 2018, 19: 643–651.

    Article  CAS  Google Scholar 

  28. Jiang P, Ma D, Wang X, Wang Y, Bi Y, Yang J, et al. Astragaloside IV prevents obesity-associated hypertension by improving pro-inflammatory reaction and leptin resistance. Mol Cells 2018, 41: 244–255.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Takahashi K, Morimoto R, Hirose T, Satoh F, Totsune K. Adrenomedullin 2/intermedin in the hypothalamo-pituitary-adrenal axis. J Mol Neurosci 2011, 43: 182–192.

    Article  CAS  Google Scholar 

  30. Hong Y, Hay DL, Quirion R, Poyner DR. The pharmacology of adrenomedullin 2/intermedin. Br J Pharmacol 2012, 166: 110–120.

    Article  CAS  Google Scholar 

  31. Zhang H, Zhang SY, Jiang C, Li Y, Xu G, Xu MJ, et al. Intermedin/adrenomedullin 2 polypeptide promotes adipose tissue browning and reduces high-fat diet-induced obesity and insulin resistance in mice. Int J Obes (Lond) 2016, 40: 852–860.

    Article  CAS  Google Scholar 

  32. Li H, Bian Y, Zhang N, Guo J, Wang C, Lau WB, et al. Intermedin protects against myocardial ischemia-reperfusion injury in diabetic rats. Cardiovasc Diabetol 2013, 12: 91.

    Article  CAS  Google Scholar 

  33. Li L, Ma P, Liu YJ, Huang C, Wai-Sum O, Tang F, et al. Intermedin attenuates LPS-induced inflammation in the rat testis. PLoS One 2013, 8: e65278.

    Article  CAS  Google Scholar 

  34. Gan XB, Sun HJ, Chen D, Zhang LL, Zhou H, Chen LY, et al. Intermedin in the paraventricular nucleus attenuates cardiac sympathetic afferent reflex in chronic heart failure rats. PLoS One 2014, 9: e94234.

    Article  Google Scholar 

  35. Wang ML, Kang YM, Li XG, Su Q, Li HB, Liu KL, et al. Central blockade of NLRP3 reduces blood pressure via regulating inflammation microenvironment and neurohormonal excitation in salt-induced prehypertensive rats. J Neuroinflammation 2018, 15: 95.

    Article  Google Scholar 

  36. Cho KH, Kim DC, Yoon CS, Ko WM, Lee SJ, Sohn JH, et al. Anti-neuroinflammatory effects of citreohybridonol involving TLR4-MyD88-mediated inhibition of NF-small ka, CyrillicB and MAPK signaling pathways in lipopolysaccharide-stimulated BV2 cells. Neurochem Int 2016, 95: 55–62.

    Article  CAS  Google Scholar 

  37. Yu Y, Wei SG, Zhang ZH, Weiss RM, Felder RB. ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction. Am J Physiol Heart Circ Physiol 2016, 310: H732–739.

    Article  Google Scholar 

  38. Beckhauser TF, Francis-Oliveira J, De Pasquale R. Reactive oxygen species: physiological and physiopathological effects on synaptic plasticity. J Exp Neurosci 2016, 10: 23–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Beckhauser TF, Francis-Oliveira J, De Pasquale R. Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-alpha, and MAP kinase signaling. J Exp Neurosci 2016, 10: 23–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ren YS, Yang JH, Zhang J, Pan CS, Yang J, Zhao J, et al. Intermedin 1-53 in central nervous system elevates arterial blood pressure in rats. Peptides 2006, 27: 74–79.

    Article  CAS  Google Scholar 

  41. Li P, Sun HJ, Han Y, Wang JJ, Zhang F, Tang CS, et al. Intermedin enhances sympathetic outflow via receptor-mediated cAMP/PKA signaling pathway in nucleus tractus solitarii of rats. Peptides 2013, 47: 1–6.

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the generous support of the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine. This work was supported by the National Natural Science Foundation of China (81000106 and 81470539).

Author information

Authors and Affiliations

  1. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, 211166, China

    Jing Sun, Xing-Sheng Ren, Ying Kang, Hang-Bing Dai, Lei Ding, Guo-Qing Zhu & Ye-Bo Zhou

  2. Department of Pathophysiology, Xuzhou Medical College, Xuzhou, 221004, China

    Lei Ding

  3. Department of Neurology, Heze Municipal Hospital, Heze, 274000, China

    Ning Tong

Authors
  1. Jing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xing-Sheng Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hang-Bing Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ning Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guo-Qing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ye-Bo Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ye-Bo Zhou.

Ethics declarations

Conflict of interest

The authors claim 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

Sun, J., Ren, XS., Kang, Y. et al. Intermedin in Paraventricular Nucleus Attenuates Sympathoexcitation and Decreases TLR4-Mediated Sympathetic Activation via Adrenomedullin Receptors in Rats with Obesity-Related Hypertension. Neurosci. Bull. 35, 34–46 (2019). https://doi.org/10.1007/s12264-018-0292-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-018-0292-9

Keywords

Search

Navigation