Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Differential gene expression of bradykinin receptors 1 and 2 in peripheral monocytes from patients with essential hypertension

Abstract

Bradykinin participates in various hypertensive processes, exerted via its type 1 and type 2 receptors (BKR1 and BKR2). The aim of the study was to investigate BKR1 and BK2R gene expression in peripheral monocytes in patients with essential hypertension compared with healthy individuals. Seventeen hypertensive patients (9 males, age 56±7 years) and 12 healthy individuals (7 males, age 55±6) participated. Mononuclear cells isolated using anti-CD14+ antibodies and mRNAs of BKR1 and BKR2 were estimated by real-time quantitative reverse transcription-PCR. Both BKR1 and BKR2 showed significantly upregulated gene expression in the group of hypertensive patients. Specifically, BKR1 gene expression was 142.1±42.2 in hypertensives versus 20.2±8 in controls (P=0.024) and BKR2 was 1222.2±361.6 in hypertensives versus 259.5±99.1 in controls (P=0.038). Antihypertensive treatment resulted in a decrease in BKR1 (from 142.1±42.2 to 55.2±17.1, P=0.065) and in BKR2 (from 1222.2±361.6 to 256.8±81.8, P=0.014) gene expression. BKR1 and BKR2 gene expression on peripheral monocytes is upregulated in essential hypertension. This may lead to functional changes in monocytes and contribute to the development of target organ damage in hypertensive patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL . International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2006; 57: 27–77.

    Article  Google Scholar 

  2. Ahluwalia A, Perretti M . B1 receptors as a new inflammatory target. Could this B the 1? Trends Pharmacol Sci 1999; 20: 100–104.

    Article  CAS  Google Scholar 

  3. Emanueli C, Bonaria Salis M, Stacca T, Pintus G, Kirchmair R, Isner JM et al. Targeting kinin B(1) receptor for therapeutic neovascularization. Circulation 2002; 105: 360–366.

    Article  CAS  Google Scholar 

  4. Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W . Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998; 101: 40–50.

    Article  CAS  PubMed Central  Google Scholar 

  5. Duka I, Kintsurashvili E, Gavras I, Johns C, Bresnahan M, Gavras H . Vasoactive potential of the B1 bradykinin receptor in normotension and hypertension. Circ Res 2001; 88: 275–281.

    Article  CAS  Google Scholar 

  6. Ignjacev-Lazich I, Kintsurashvili E, Johns C, Vitseva O, Duka A, Shenouda S et al. Angiotensin-converting enzyme regulates bradykinin receptor gene expression. Am J Physiol Heart Circ Physiol 2005; 289: H1814–H1820.

    Article  CAS  Google Scholar 

  7. Dörffel Y, Franz S, Pruss A, Neumann G, Rohde W, Burmester GR et al. Preactivated monocytes from hypertensive patients as a factor for atherosclerosis? Atherosclerosis 2001; 157: 151–160.

    Article  PubMed Central  Google Scholar 

  8. Ghattas A, Griffiths HR, Devitt A, Lip GY, Shantsila E . Monocytes in coronary artery disease and atherosclerosis: where are we now? J Am Coll Cardiol 2013; 62: 1541–1551.

    Article  CAS  Google Scholar 

  9. Hillmeister P, Gatzke N, Dülsner A, Bader M, Schadock I, Hoefer I et al. Arteriogenesis is modulated by bradykinin receptor signaling. Circ Res 2011; 109: 524–533.

    Article  CAS  PubMed Central  Google Scholar 

  10. Belanger S, Bovenzi V, Côté J, Neugebauer W, Amblard M, Martinez J et al. Structure-activity relationships of novel peptide agonists of the human bradykinin B2 receptor. Peptides 2009; 30: 777–787.

    Article  CAS  Google Scholar 

  11. Ignjatovic T, Stanisavljevic S, Brovkovych V, Skidgel RA, Erdös EG . Kinin B1 receptors stimulate nitric oxide production in endothelial cells: signaling pathways activated by angiotensin I-converting enzyme inhibitors and peptide ligands. Mol Pharmacol 2004; 66: 1310–1316.

    Article  CAS  Google Scholar 

  12. Lagneux C, Bader M, Pesquero JB, Demenge P, Ribuot C . Detrimental implication of B1 receptors in myocardial ischemia: evidence from pharmacological blockade and gene knockout mice. Int Immunopharmacol 2002; 2: 815–822.

    Article  CAS  Google Scholar 

  13. Böckmann S, Paegelow I . Kinins and kinin receptors: importance for the activation of leukocytes. J Leukoc Biol 2000; 68: 587–592.

    PubMed  Google Scholar 

  14. Bertram CM, Baltic S, Misso NL, Bhoola KD, Foster PS, Thompson PJ et al. Expression of kinin B1 and B2 receptors in immature, monocyte-derived dendritic cells and bradykinin-mediated increase in intracellular Ca2+ and cell migration. J Leukoc Biol 2007; 81: 1445–1454.

    Article  CAS  Google Scholar 

  15. Dos Santos AC, Roffê E, Arantes RM, Juliano L, Pesquero JL, Pesquero JB et al. Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice. J Neuroinflamm 2008; 5: 49.

    Article  Google Scholar 

  16. Kränkel N, Katare RG, Siragusa M, Barcelos LS, Campagnolo P, Mangialardi G et al. Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential. Circ Res 2008; 103: 1335–1343.

    Article  PubMed Central  Google Scholar 

  17. Phagoo SB, Poole S, Leeb-Lundberg LM . Autoregulation of bradykinin receptors: agonists in the presence of interleukin-1beta shift the repertoire of receptor subtypes from B2 to B1 in human lung fibroblasts. Mol Pharmacol 1999; 56: 325–333.

    Article  CAS  Google Scholar 

  18. Leeb-Lundberg LM, Kang DS, Lamb ME, Fathy DB . The human B1 bradykinin receptor exhibits high ligand-independent, constitutive activity: roles of residues in the fourth intracellular and third transmembrane domains. J Biol Chem 2001; 276: 8785–8792.

    Article  CAS  Google Scholar 

  19. Dabek J, Wilczok T, Gasior Z, Kucia-Kuzma S, Twardowski R, Kulach A . Gene expression of kinin receptors B1 and B2 in PBMC from patients with cardiac syndrome X. Scand Cardiovasc 2007; 41: 391–396.

    Article  CAS  Google Scholar 

  20. Dabek J, Kulach A, Smolka G, Wilczok T, Scieszka J, Gasior Z . Expression of genes encoding kinin receptors in peripheral blood mononuclear cells from patients with acute coronary syndromes. Intern Med J 2008; 38: 892–896.

    Article  CAS  PubMed Central  Google Scholar 

  21. Bourdet B, Pécher C, Minville V, Jaafar A, Allard J, Blaes N et al. Distribution and expression of B2-kinin receptor on human leukocyte subsets in young adults and elderly using flow cytometry. Neuropeptides 2010; 44: 155–161.

    Article  CAS  PubMed Central  Google Scholar 

  22. Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ . Effect of bradykinin-receptor blockade on the response to angiotensin-converting enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998; 339: 1285–1292.

    Article  CAS  PubMed Central  Google Scholar 

  23. Witherow FN, Dawson P, Ludlam CA, Fox KA, Newby DE . Marked bradykinin-induced tissue plasminogen activator release in patients with heart failure maintained on long-term angiotensin-converting enzyme inhibitor therapy. J Am Coll Cardiol 2002; 40: 961–966.

    Article  CAS  PubMed Central  Google Scholar 

  24. Pretorius M, Rosenbaum D, Vaughan DE, Brown NJ . Angiotensin converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin. Circulation 2003; 107: 579–585.

    Article  PubMed Central  Google Scholar 

  25. Souza DG, Lomez ES, Pinho V, Pesquero JB, Bader M, Pesquero JL et al. Role of bradykinin B2 and B1 receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury. J Immunol 2004; 172: 2542–2548.

    Article  CAS  PubMed Central  Google Scholar 

  26. Guevara-Lora I, Florkowska M, Kozik A . Bradykinin-related peptides up-regulate the expression of kinin B1 and B2 receptor genes in human promonocytic cell line U937. Act Bioch Pol 2009; 56: 515–522.

    CAS  Google Scholar 

  27. Leibowitz A, Schiffrin EL . Immune mechanisms in hypertension. Curr Hypertens Rep 2011; 13: 465–472.

    Article  CAS  PubMed Central  Google Scholar 

  28. Duka A, Kintsurashvili E, Duka I, Ona D, Hopkins TA, Bader M et al. Angiotensin-converting enzyme inhibition after experimental myocardial infarct: role of the kinin B1 and B2 receptors. Hypertension 2008; 51: 1352–1357.

    Article  CAS  PubMed Central  Google Scholar 

  29. Kintsurashvili E, Duka I, Gavras I, Johns C, Farmakiotis D, Gavras H . Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2001; 281: H1778–H1783.

    Article  CAS  PubMed Central  Google Scholar 

  30. Fernandes L, Ceravolo GS, Fortes ZB, Tostes R, Santos RA, Santos JA et al. Modulation of kinin B1 receptor expression by endogenous angiotensin II in hypertensive rats. Regul Pept 2006; 136: 92–97.

    Article  CAS  Google Scholar 

  31. Shen B, Harrison-Bernard LM, Fuller AJ, Vanderpool V, Saifudeen Z, El-Dahr SS . The bradykinin B2 receptor gene is a target of angiotensin II type 1 receptor signaling. J Am Soc Nephrol 2007; 18: 1140–1149.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr Fernand Gobeil from Sherbrooke University, Canada, for providing us with the selective BKR2-agonist. This work was supported by an award from the Hellenic Cardiological Society.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M E Marketou.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marketou, M., Kontaraki, J., Zacharis, E. et al. Differential gene expression of bradykinin receptors 1 and 2 in peripheral monocytes from patients with essential hypertension. J Hum Hypertens 28, 450–455 (2014). https://doi.org/10.1038/jhh.2013.133

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2013.133

Keywords

This article is cited by

Search

Quick links