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.

  • Opinion
  • Published:

Autoimmunity in the pathogenesis of hypertension

Abstract

Hypertension affects more than one-third of the adult population of the world. However, the cause of high blood pressure is unknown in the vast majority of patients, classified as patients with essential hypertension. Evidence accumulated over the past decade supports the participation of inflammation in the development of experimental hypertension. Investigations have also demonstrated that immune reactivity to overexpressed heat shock protein 70 (HSP70) is involved in the pathogenesis of salt-induced hypertension. This article reviews, first, the role of T cell-induced inflammation in the arteries, kidney and central nervous system in hypertension and the amelioration of hypertension induced by regulatory T cells. Second, experiments showing that autoimmunity directed to HSP70 in the kidney impairs the pressure natriuresis relationship and has a pivotal role in the pathogenesis of salt sensitive hypertension. Finally, we highlight the clinical evidence that supports the participation of autoimmunity in essential hypertension.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Autoimmunity in hypertension—a role for HSP70.

Similar content being viewed by others

References

  1. Ryan, M. J. An update on immune system activation in the pathogenesis of hypertension. Hypertension 62, 226–230 (2013).

    CAS  PubMed  Google Scholar 

  2. Marvar, P. J. & Harrison, D. G. Stress-dependent hypertension and the role of T lymphocytes. Exp. Physiol. 97, 1161–1167 (2012).

    PubMed  PubMed Central  Google Scholar 

  3. Harrison, D. G., Marvar, P. J. & Titze, J. M. Vascular inflammatory cells in hypertension. Front. Physiol. 3, 128 http://dx.doi.org/10.3389/fphys.2012.00128.

  4. Leibowitz, A. & Schiffrin, E. L. Immune mechanisms in hypertension. Curr. Hypertens. Rep. 13, 465–472 (2011).

    CAS  PubMed  Google Scholar 

  5. Muller, D. N., Kvakan, H. & Luft, F. C. Immune-related effects in hypertension and target-organ damage. Curr. Opin. Nephrol. Hypertens. 20, 113–117 (2011).

    CAS  PubMed  Google Scholar 

  6. Harrison, D. G. et al. Inflammation, immunity, and hypertension. Hypertension 57, 132–140 (2011).

    CAS  PubMed  Google Scholar 

  7. Rodríguez-Iturbe, B., Franco, M., Tapia, E., Quiroz, Y. & Johnson, R. J. Renal inflammation, autoimmunity and salt-sensitive hypertension. Clin. Exp. Pharmacol. Physiol. 39, 96–103 (2012).

    PubMed  PubMed Central  Google Scholar 

  8. Rodríguez-Iturbe, B. & Johnson, R. J. The role of microvascular disease and interstitial inflammation in salt-sensitive hypertension. Hypertens. Res. 33, 975–980 (2010).

    PubMed  Google Scholar 

  9. Bendich, A., Belisle, E. H. & Strausser, H. R. Immune system modulation and its effects on blood pressure of the spontaneously hypertensive male and female rat. Biochem. Biophys. Res. Commun. 99, 600–607 (1981).

    CAS  PubMed  Google Scholar 

  10. Olsen, F. Transfer of arterial hypertension by splenic cells from DOCA-salt hypertensive and renal hypertensive rats to normotensive recipients. Acta Pathol. Microbiol. Scand. C 88, 1–5 (1980).

    CAS  PubMed  Google Scholar 

  11. Svendsen, U. G. Evidence for an initial, thymus independent and a chronic, thymus dependent phase of DOCA and salt hypertension in mice. Acta Pathol. Microbiol. Scand. A 84, 523–528 (1976).

    CAS  PubMed  Google Scholar 

  12. Ba, D., Takeichi, N., Kodama, T. & Kobayashi, H. Restoration of T cell depression and suppression of blood pressure in spontaneously hypertensive rats (SHR) by thymus grafts or thymus extracts. J. Immunol. 128, 1211–1216 (1982).

    CAS  PubMed  Google Scholar 

  13. Tuttle, R. S. & Boppana, D. P. Antihypertensive effect of interleukin-2. Hypertension 15, 89–94 (1990).

    CAS  PubMed  Google Scholar 

  14. Dzielak, D. J. AIDS, lupus, rheumatoid arthritis—hypertension. Hypertension 15, 95–96 (1990).

    CAS  PubMed  Google Scholar 

  15. Guzik, T. J. et al. Role of T cell in the genesis of angiotensin II-induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449–2460 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kasal, D. A. et al. T regulatory lymphocytes prevent aldosterone-induced vascular injury. Hypertension 59, 324–330 (2012).

    CAS  PubMed  Google Scholar 

  17. Marvar, P. J. et al. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ. Res. 107, 263–270 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zimmerman, M. C. et al. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ. Res. 91, 1038–1045 (2002).

    CAS  PubMed  Google Scholar 

  19. Lob, H. E. et al. Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system. Hypertension 55, 277–283 (2010).

    CAS  PubMed  Google Scholar 

  20. Shi, P. et al. Microglial cytokines in neurogenic hypertension. Hypertension 56, 297–303 (2010).

    CAS  PubMed  Google Scholar 

  21. Franco, M. et al. Impaired pressure natriuresis resulting in salt-sensitive hypertension is caused by tubulointerstitial immune cell infiltration in the kidney. Am. J. Physiol. Renal Physiol. 304, F982–F990 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Franco, M. et al. Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension. Am. J. Physiol. Reg. Integr. Comp. Physiol. 293, R251–R256 (2007).

    CAS  Google Scholar 

  23. Rodríguez-Iturbe, B., Quiroz, Y., Ferrebuz, A., Parra, G. & Vaziri, N. D. Evolution of renal interstitial inflammation and NF-kB activation in spontaneously hypertensive rats. Am. J. Nephrol. 24, 587–594 (2004).

    PubMed  Google Scholar 

  24. Rodríguez-Iturbe, B. et al. Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats. Am. J. Physiol. Renal Physiol. 282, F191–F201 (2002).

    PubMed  Google Scholar 

  25. De Miguel, C., Guo, C., Lund, H., Feng, D. & Mattson, D. L. Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease. Am. J. Physiol. Renal Physiol. 300, F734–F742 (2011).

    CAS  PubMed  Google Scholar 

  26. Alvarez, V., Quiroz, Y., Nava, M., Pons, H. & Rodríguez-Iturbe, B. Overload proteinuria is followed by salt-sensitive hypertension caused by renal infiltration of immune cells. Am. J. Physiol. Renal Physiol. 283, F1132–F1141 (2002).

    PubMed  Google Scholar 

  27. Vanegas, V., Ferrebuz, A., Quiroz, Y. & Rodríguez-Iturbe, B. Hypertension in Page (cellophane wrapped) kidney is due to interstitial nephritis. Kidney Int. 68, 1161–1170 (2005).

    PubMed  Google Scholar 

  28. Madhur, M. S. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 55, 500–507 (2010).

    CAS  PubMed  Google Scholar 

  29. Mattson, D. L. et al. Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage. Am. J. Physiol. Regul. Integr.Comp. Physiol. 304, R407–R414 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Basu, R., Hatton, R. D. & Weaver, C. T. The Th17 family: flexibility follows function. Immunol. Rev. 252, 89–103 (2013).

    PubMed  PubMed Central  Google Scholar 

  31. Gratze, P. et al. Novel role for inhibitor of differentiation 2 in the genesis of angiotensin II-induced hypertension. Circulation 117, 2645–2656 (2008).

    CAS  PubMed  Google Scholar 

  32. Viel, E. C., Lemarié, C. A., Benkirane, K., Paradis, P. & Schiffrin, E. L. Immune regulation and vascular inflammation in genetic hypertension. Am. J. Physiol. Heart Circ. Physiol. 298, H938–H944 (2010).

    CAS  PubMed  Google Scholar 

  33. Barhoumi, T. et al. T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. Hypertension 57, 469–476 (2011).

    CAS  PubMed  Google Scholar 

  34. Chiasson, V. L. et al. FK506 binding protein 12 deficiency in endothelial and hematopoietic cells decreases regulatory T cells and causes hypertension. Hypertension 57, 1167–1175 (2011).

    CAS  PubMed  Google Scholar 

  35. Rodríguez-Iturbe, B., Zhan, C.-D., Quiroz, Y., Sindhu, R., K & Vaziri, N. D. Antioxidant-rich diet improves hypertension and reduces renal immune infiltration in spontaneously hypertensive rats. Hypertension 41, 341–346 (2003).

    PubMed  Google Scholar 

  36. Herrada, A. A. et al. Aldosterone as a modulator of immunity: implications in the organ damage. J. Hypertens. 29, 1684–1692 (2011).

    CAS  PubMed  Google Scholar 

  37. Gonzalez-Villalobos, R. A. et al. The absence of intrarenal ACE protects against hypertension. J. Clin. Invest. 123, 2011–2023 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Crowley, S. D. et al. A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotenin II-dependent hypertension. Hypertension 55, 99–108 (2010).

    CAS  PubMed  Google Scholar 

  39. Guyton, A. C. et al. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am. J. Med. 52, 584–594 (1972).

    CAS  PubMed  Google Scholar 

  40. Titze, J. & Matchnik, A. Sodium sensing in the interstitium and relationship to hypertension. Curr. Opin. Nephrol. Hypertens. 19, 385–392 (2010).

    PubMed  Google Scholar 

  41. Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C dependent buffering mechanism. Nat. Med. 15, 545–552 (2009).

    CAS  PubMed  Google Scholar 

  42. Wiig, H. et al. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J. Clin. Invest. 123, 2803–2815 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Rodríguez-Iturbe, B., Vaziri, N. D., Herrera-Acosta, J. & Johnson, R. J. Oxidative stress, renal infiltration of immune cells and salt-sensitive hypertension: all for one and one for all. Am. J. Physiol. Renal Physiol. 286, F606–F616 (2004).

    PubMed  Google Scholar 

  44. Bravo, J. et al. Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition. Kidney Int. 64 (Suppl. 86), S46–S51 (2003).

    Google Scholar 

  45. Ishizaka, N. et al. Regulation and localization of HSP70 and HSP25 in the kidney of rats undergoing long-term administration of angiotensin II. Hypertension 39, 122–128 (2002).

    CAS  PubMed  Google Scholar 

  46. Udelsman, R. et al. Vascular heat shock protein expression response to stress. J. Clin. Invest. 91, 465–473 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mazurek, B., Haupt, H., Klapp, B. F., Szczepek, A. J. & Olze, H. Exposure of Wistar rats to 24-h psycho-social stress alters gene expression in the inferior colliculus. Neurosci. Lett. 527, 40–45 (2012).

    CAS  PubMed  Google Scholar 

  48. Todryk, S. M., Gough, M. J. & Pockley, A. G. Facets of heat shock protein 70 show immunotherapeutic potential. Immunology 110, 1–9 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Parra, G. et al. Experimental induction of salt-sensitive hypertension is associated with lymphocyte proliferative response to HSP70. Kidney Int. Suppl. 111, S55–S59 (2008).

    CAS  Google Scholar 

  50. Quiroz, Y. et al. Mycophenolate mofetil prevents the salt-sensitive hypertension resulting from short-term nitric oxide synthesis inhibition. Am. J. Physiol. Renal Physiol. 281, F38–F47 (2001).

    CAS  PubMed  Google Scholar 

  51. Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wendling, U. et al. A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian self-hsp70 homologue. J. Immunol. 164, 2711–2717 (2000).

    CAS  PubMed  Google Scholar 

  54. Prakken, B. J. et al. Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionary conserved immunodominant proteins. J. Immunol. 167, 4147–4153 (2001).

    CAS  PubMed  Google Scholar 

  55. Pons, H. et al. Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt sensitive hypertension. Am. J. Physiol. Renal Physiol. 304, F289–F299 (2013).

    CAS  PubMed  Google Scholar 

  56. Boursier, G., Siri, A. & de Boysson, H. Utilisation des lymphocytes T régulateurs en thérapies cellulaires dans les maladies auto-immunes [French]. Med. Sci. (Paris) 28, 757–763 (2012).

    Google Scholar 

  57. Vinh, A. et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 122, 2529–2537 (2010).

    PubMed  PubMed Central  Google Scholar 

  58. Gareau, R. J. & Cartier, G. E. Étude histologique de 55 biopsies rénales prélevées chez maladies hypertendus [French]. Union Med. Can. 84, 1134–1142 (1955).

    CAS  PubMed  Google Scholar 

  59. Heptinstall, R. H. Renal biopsies in hypertension. Br. Heart J. 16, 133–141 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sommers, S. C., Relman, A. S. & Smithwick, R. H. Histologic studies of kidney biopsy specimens from patients with hypertension. Am. J. Pathol. 34, 685–715 (1954).

    Google Scholar 

  61. Hughson, M. D. et al. Associations of glomerular number and birth weight with clinicopathological features of African Americans and whites. Am. J. Kidney Dis. 52, 18–28 (2008).

    PubMed  Google Scholar 

  62. Lefkos, N. et al. Immunopathogenic mechanisms in hypertension. Am. J. Hypertens. 8, 1141–1145 (1995).

    CAS  PubMed  Google Scholar 

  63. Stumpf, C. et al. Serum levels of the Th1 chemoattractant interferon-gamma-inducible protein (IP) 10 are elevated in patients with essential hypertension. Hypertens. Res. 34, 484–488 (2011).

    CAS  PubMed  Google Scholar 

  64. Herrera, J., Ferrebuz, A., García-Macgregor, E. & Rodríguez-Iturbe, B. Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. J. Am. Soc. Nephrol. 17, S218–S225 (2006).

    CAS  PubMed  Google Scholar 

  65. Seaberg, E. C. et al. Multicenter AIDS Cohort Study. Association between highly active antiretroviral therapy and hypertension in a large cohort of men followed from 1984 to 2003. AIDS 19, 953–960 (2005).

    PubMed  Google Scholar 

  66. Pockley, A. G., Georgiades, A., Thulin, T., de Faire, U. & Frostegård, J. Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42, 235–238 (2003).

    CAS  PubMed  Google Scholar 

  67. Pockley, A. G. et al. Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J. Hypertens. 20, 1815–1829 (2002).

    CAS  PubMed  Google Scholar 

  68. Kunes, J., Poirier, M., Tremblay, J. & Hamet, P. Expression of HSP70 gene in lymphocytes from normotensive and hypertensive humans. Acta Physiol. Scand. 146, 307–311 (1992).

    CAS  PubMed  Google Scholar 

  69. Li, J. X. et al. Interacting contribution of the five polymorphisms in three genes of Hsp70 family to essential hypertension in Uygur ethnicity. Cell Stress Chaperones 14, 355–362 (2009).

    CAS  PubMed  Google Scholar 

  70. Marketou, M. E. et al. TLR2 and TLR4 gene expression in peripheral monocytes in nondiabetic hypertensive patients: the effect of intensive blood pressure-lowering. J. Clin. Hypertens. (Greenwich) 14, 330–335 (2012).

    CAS  Google Scholar 

  71. Mattson, D. L., James. L., Berdan. E. A. & Meister, C. J. Immune suppression attenuates hypertension and renal disease in Dahl salt hypertensive rats. Hypertension 48, 149–156 (2006).

    CAS  PubMed  Google Scholar 

  72. Tian, N. et al. Immune suppression prevents renal damage and dysfunction and reduces arterial pressure in salt-sensitive hypertension. Am. J. Physiol. Heart Circ. Physiol. 292, H1018–H1022 (2007).

    CAS  PubMed  Google Scholar 

  73. Stewart, T., Jung, F. F., Manning, J. & Vehaskari, V. M. Kidney immune cell infiltration and oxidative stress contribute to prenatally programmed hypertension. Kidney Int. 68, 2180–2188 (2005).

    CAS  PubMed  Google Scholar 

  74. Rodríguez-Iturbe, B. et al. Early and sustained inhibition of nuclear factor-κB prevents hypertension in spontaneously hypertensive rats. J. Pharmacol. Exp. Ther. 315, 51–57 (2005).

    PubMed  Google Scholar 

  75. Müller, D. N. et al. NF-κB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 35 (Part 2), 193–201 (2000).

    PubMed  Google Scholar 

  76. Müller, D. N. et al. Immunosuppressive treatment protects against angiotensin-II induced renal damage. Am. J. Pathol. 161, 1679–1690 (2002).

    PubMed  PubMed Central  Google Scholar 

  77. Khraibi, A. A., Norman, R. A. Jr & Dzielak, D. J. Chronic immunosuppression attenuates hypertension in Okamoto spontaneously hypertensive rats. Am. J. Physiol. 247, H722–H726 (1984).

    CAS  PubMed  Google Scholar 

  78. Norman, R. A. Jr, Galloway, P. G., Dzielak, D. J. & Huang, M. Mechanisms of partial renal infarct hypertension. J. Hypertens. 6, 397–403 (1988).

    PubMed  Google Scholar 

  79. Svendsen, J. G. Spontaneous hypertension and hypertensive vascular disease in the NZB strain of mice. Acta Pathol. Microbiol. Scand. A 85, 261–268 (1977).

    Google Scholar 

  80. Svendsen, U. G. The importance of thymus in the pathogenesis of the chronic phase of hypertension in mice following partial infarction of the kidney. Acta Pathol. Microbiol. Scand. A 85, 539–547 (1977).

    CAS  PubMed  Google Scholar 

  81. Bataillard, P., Freiche, J.-C., Vincent, M., Touraine, J.-L. & Sassard, J. U. Effects of neonatal thymectomy on blood pressure and immunological characteristics of the genetically hypertensive rats of the Lyon strain. J. Hypertens. 4 (Suppl. 3), 5455–5467 (1986).

    Google Scholar 

  82. Bomfim, G. F. et al. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin. Sci. (Lond.) 122, 535–543 (2012).

    CAS  Google Scholar 

  83. Delves, P. J. in Essential Immunology 12th edn (ed. Roitt, P. J.) 475–510 (Wiley–Blackwell, 2011).

    Google Scholar 

Download references

Acknowledgements

Work in the authors' laboratories is supported by funding from grants from FONACYT, Venezuela (FC-2005000283, to B. Rodríguez-Iturbe) and the National Institutes of Health National Heart Lung and Blood Institute, USA (HL-68607, to R. J. Johnson).

Author information

Authors and Affiliations

Authors

Contributions

B. Rodríguez-Iturbe, H. Pons, Y. Quiroz and R. J. Johnson researched data for the article. B. Rodríguez-Iturbe and R. J. Johnson wrote the article and made substantial contribution to discussion of the content. M. A. Lanaspa also made substantial contribution to discussion of the content. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Bernardo Rodríguez-Iturbe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodríguez-Iturbe, B., Pons, H., Quiroz, Y. et al. Autoimmunity in the pathogenesis of hypertension. Nat Rev Nephrol 10, 56–62 (2014). https://doi.org/10.1038/nrneph.2013.248

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2013.248

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing