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.

  • Research Letter
  • Published:

Linking inflammation and hypertension in humans: studies in Bartter's/Gitelman's syndrome patients

Journal of Human Hypertension volume 22, pages 223–225 (2008)Cite this article

Inflammation and the relationship between inflammation, angiotensin II (Ang II) and its signalling have been recognized as playing a critical role in hypertension and atherosclerosis, but few data are available in humans. We explored in Bartter's/Gitelman's syndrome (BS/GS) patients, who do not develop hypertension and related cardiovascular remodelling and atherosclerosis despite high Ang II levels, the inflammation status through the evaluation of factors included in Ang II signalling involved in inflammation, and found unchanged phosphorylated extracellular signal-regulated kinase (pERK)/ERK ratio and p66 shc compared to controls while IκB, the inhibitory subunit of nuclear factor-κB, was increased. This, together with the unchanged level of inflammatory markers that we previously reported in BS/GS, depicts a picture opposite to that of hypertension and indirectly supports a link between inflammation and hypertension.

Hypertension and atherosclerosis are thought as diseases in which inflammation plays a central role.1, 2 The development and progression of these diseases are in fact associated with increased expression and production of pro-inflammatory mediators, including cytokines, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, monocyte chemotactic protein-1, nuclear factor-κB (NF-κB) and growth factors.1, 2 Both inflammation and Ang II are involved in the pathogenesis of cardiovascular and renal diseases, and Ang II itself is a powerful pro-inflammatory cytokine and growth factor.3, 4 In addition, Ang II activates NF-κB, a key nuclear transcription factor in inflammation and fibrosis, and this activation leads to the release of downstream inflammatory signalling molecules and induction of oxidative stress, tightly linked with inflammation.3, 4 The possibility of confirming this mechanism in humans could come from the study of a human model for vascular tone and structure regulation, which has biochemical and hormonal characteristics typical of hypertension, yet shows hyporesponsiveness to pressors, reduced vascular resistance and normo/hypotension such as BS/GS.5, 6 Our extensive series of studies have, in fact, provided mechanistic explanations for the vascular hyporeactivity typical of these patients and also led us to propose that BS/GS is a good human model to explore the mechanisms responsible for Ang II signalling.5, 6 In BS/GS, we have demonstrated that the Ang II signalling pathway is blunted as documented by the increased regulator of G-protein signalling-2 gene and protein expression, reduced gene and protein expression of the α-subunit of the Gq-binding protein, which transduces Ang II signal, and reduced related downstream cellular events such as intracellular Ca2+ and IP3 release and PKC activity.5, 6 This abnormal G-protein-mediated signalling of Ang II shown in BS/GS patients, combined with downregulation of RhoA/Rho-kinase pathway7 and upregulation of NO system,5, 6 reduced peripheral resistance, vascular hyporeactivity, normo/hypotension typical of these patients and their collection of biochemical characteristics, presents a mirror image of that found in hypertension. In addition, BS/GS patients have unchanged levels of C-reactive protein, serum amyloid A, vascular cell adhesion molecule, intercellular adhesion molecule, interleukin-6 and tumor necrosis factor-α.8 This in the presence of high levels of Ang II and upregulated activity of the NO system again suggests that BS/GS is the mirror image of hypertension, and further stresses the critical role of Ang II in inflammation-related processes. The current study extends our findings, determining in our cohort of extensively characterized 12 BS/GS patients, 2 BS and 10 GS,5, 6, 7, 8 the levels of another set of pathways involved in Ang II signalling in inflammation such as ERK, IκB, the inhibitory subunit of NF-κB, and p66shc, adaptor protein involved in the response to oxidative stress. Twelve sex- and age-matched normotensive healthy subjects from the staff of the Department of Clinical and Experimental Medicine at the University of Padova were used as controls. None of the patients or controls took drugs for at least 2 weeks prior to the study and all abstained from food, alcohol and caffeine-containing drinks for at least 12 h prior to sample collection. Mononuclear cell ERK-1 and ERK-2 phosphorylation and IκB protein content were evaluated using western blot analysis, while p66shc gene expression was evaluated using reverse transcription-PCR. Their quantification was done using NIH image software through the ratio between phosphorylated ERK-1/2 and ERK-1/2 as indexes of ERK-1/2 activation, the ratio between IκB-α and glyceraldehyde-3-phosphate dehydrogenase as an index of IκB-α protein content and the ratio between p66shc and glyceraldehyde-3-phosphate dehydrogenase PCR products as an index of p66shc gene expression.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

References

  1. Hansson GK . Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685–1695.

    Article  CAS  Google Scholar 

  2. Pauletto P, Rattazzi M . Inflammation and hypertension: the search for a link. Nephrol Dial Transplant 2006; 21: 850–853.

    Article  Google Scholar 

  3. Das UN . Is angiotensin II an endogenous pro-inflammatory molecule? Med Sci Monit 2005; 11: 155–162.

    Google Scholar 

  4. Lassegue B, Griendling KK . Reactive oxygen species in hypertension. Am J Hypertens 2004; 17: 852–860.

    Article  CAS  Google Scholar 

  5. Cal LA, Pessina AC, Semplicini A . Angiotensin II signaling in the Bartter's and Gitelman's syndromes, a negative human model of hypertension. High Blood Press Cardiovasc Prev 2005; 12: 17–26.

    Article  Google Scholar 

  6. Calò LA . Vascular tone control in humans: the utility of studies in Bartter's/Gitelman's syndromes. Kidney Int 2006; 69: 963–966.

    Article  Google Scholar 

  7. Calò LA, Pessina AC . RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. J Hypertens 2007; 25: 259–264.

    Article  Google Scholar 

  8. Davis PA, Mussap M, Pagnin E, Bertipaglia L, Savica V, Semplicini A et al. Early markers of inflammation in a high angiotensin II state. Results of studies in Bartter's/Gitelman's syndromes. Nephrol Dial Transplant 2006; 21: 1697–1701.

    Article  CAS  Google Scholar 

  9. Mehta PK, Griendling KK . Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007; 292: C82–C97.

    Article  CAS  Google Scholar 

  10. Semplicini A, Lenzini L, Sartori M, Papparella I, Calo LA, Pagnin E et al. Reduced expression of regulator of G-protein signaling 2 (RGS2) in hypertensive patients increases calcium mobilization and ERK1/2 phosphorylation induced by angiotensin II. J Hypertens 2006; 24: 1115–1124.

    Article  CAS  Google Scholar 

  11. Graiani G, Lagrasta C, Migliaccio E, Spillmann F, Meloni M, Madeddu P et al. Genetic deletion of the p66Shc adaptor protein protects from angiotensin II-induced myocardial damage. Hypertension 2005; 46: 433–440.

    Article  CAS  Google Scholar 

  12. de Winther MP, Kanters E, Kraal G, Hofker MH . Nuclear factor kappa B signaling in atherogenesis. Arterioscler Thromb Vasc Biol 2005; 25: 904–914.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy

    L A Caló, E Pagnin, S Schiavo, A Semplicini & A C Pessina

  2. Department of Nutrition, University of California, Davis, Davis, CA, USA

    P A Davis

Authors
  1. L A Caló
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P A Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Pagnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Schiavo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Semplicini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A C Pessina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L A Caló.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Caló, L., Davis, P., Pagnin, E. et al. Linking inflammation and hypertension in humans: studies in Bartter's/Gitelman's syndrome patients. J Hum Hypertens 22, 223–225 (2008). https://doi.org/10.1038/sj.jhh.1002309

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jhh.1002309

This article is cited by

Search

Advanced search

Quick links