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NDT Advance Access originally published online on April 12, 2006
Nephrology Dialysis Transplantation 2006 21(8):2340-2342; doi:10.1093/ndt/gfl173
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Letter

The search for a link between inflammation and hypertension—contribution from Bartter's/Gitelman's syndromes

Email: renzcalo{at}unipd.it

Sir,

The involvement of inflammation and its mediators in cardiovascular pathophysiology and atherogenesis is increasingly recognized [1]. Plasma level of inflammatory molecules such as C-reactive protein (CRP); cytokines, such as tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6); chemokines, such as monocyte chemoattractant protein (MCP-1) and adhesion molecules, such as P-selectin and leucocyte adhesion molecules, intercellular adhesion molecules (ICAM-1), are increased in patients with essential hypertension [2–4] and increased CRP level has also been reported to be a predictor of future cardiovascular disease [5,6]. In addition, further emphasising the involvement of inflammation and its mediators in cardiovascular pathophysiology is the importance of the search for a possible pathophysiological link between inflammation and hypertension; however, this awaits definitive clarification. Recent epidemiological observation of a systemic low inflammatory status preceding the onset of essential hypertension [7] strengthens this possibility, and thus stimulates the search for evidence that inflammation can promote hypertension. This issue was recently reviewed and discussed by Pauletto and Rattazzi [7] in their editorial comment published in NDT, which we read with great interest. These authors reviewed data from the literature and from their laboratory, supporting the possibility of a pathophysiological link between inflammation, hypertension and long-term complication such as atherogenesis [7]. The expression and plasma level of CRP, TNF-{alpha}, IL-6, MCP-1, P-selectin and ICAM-1 have been reported to be increased in these conditions and linked with nuclear transcription factor kappa B (NF{kappa}B) system activation [7]. Suggested mechanisms for the increase of these molecules and the activation of NF{kappa}B include the pro-inflammatory effect of angiotensin II (Ang II) via induction of NF{kappa}B, stimulation of NADPH oxidase activity with increased production of reactive oxygen species and oxidative stress followed by reduction of NO bioavailability, endothelial dysfunction and impairment of endothelial-dependent vasodilation [8].

Recent results from our ongoing studies in patients with Bartter's/Gitelman's syndromes (BS/GS) provide additional support and evidence for the existence and importance of a relationship between inflammation and hypertension. Of direct relevance is our recent demonstration in BS/GS patients of unchanged CRP plasma level, as well as acute phase reactants such as serum amyloid A, vascular cell adhesion molecules (VCAM) and ICAM, and inflammatory process-related cytokines such as IL-6 and TNF-{alpha} compared with healthy subjects [9]. BS/GS, caused by gene defects in specific kidney transporters and ion channels, present a puzzling clinical picture characterized by hypokalaemia, sodium depletion, activation of the renin–angiotensin–aldosterone system (RAAS), with increased plasma levels of Ang II and aldosterone, yet normo/hypotension, reduced peripheral resistance and hyporesponsiveness to pressor agents [10]. BS/GS have been considered a good human model to explore the mechanisms responsible for maintenance/controlling vascular tone and vascular remodelling [10,11]. In fact, understanding why patients with BS/GS do not develop hypertension and its complications such as cardiovascular remodelling and atherogenesis in spite of high Ang II and activation of RAAS, sheds considerable light on the cellular basis of hypertension. In BS/GS specifically, the short-term Ang II signalling pathway is blunted as documented by the increased regulator of G-protein signalling-2 [12] reduced G{alpha}q gene and protein expression [13,14], and reduced related downstream cellular events such as intracellular Ca2+ and IP3 release, and PKC activity [10]. The long-term signalling pathway of Ang II, which modulates the cell redox state to promote cardiovascular remodelling and atherosclerosis, is also altered in BS/GS (reduced gene expression and response to Ang II of p22phox, TGF-ß and reduced low density lipoproteins oxidative susceptibility and increased antioxidant power) [10,15,16]. We have also reported that RhoA/Rho kinase pathway is blunted, as shown by the reduced gene and protein expression and response to Ang II challenge of Rho kinase and plasminogen activator inhibitor-1 (PAI-1) [17], and by the reduced gene and protein expression of the upstream regulator of RhoA, p115RhoGEF [18]. The down-regulation of Rho/Rho kinase pathway occurred in a context of the increased level of the endothelial subunit of NO synthase (eNOS) mRNA alongside elevated urinary NO metabolites and cGMP levels [19,20]. Therefore, the reduced peripheral resistance, vascular hyporeactivity and normohypotension typical of BS/GS patients and their collection of biochemical characteristics present a mirror image of those found in hypertension. In addition, the BS/GS patients’ unchanged level of CRP and other inflammatory mediators included VCAM, ICAM, IL-6 and TNF-{alpha} [9], whose expression is known to be dependent of NF{kappa}B activity, also provide, in a human model of altered vascular tone regulation, confirmatory data in support of a relationship between inflammation and hypertension. In fact, evidence has been recently provided for the involvement of Rho/Rho-kinase signalling in CRP-induced atherothrombogenesis. CRP has been shown to activate Rho/Rho-kinase signalling, which through activation of NF{kappa}B activity results in PAI-1 expression, a known atherothrombogenic factor [21]. One possible mechanism for the CRP-mediated activation of NF{kappa}B is through the RhoA-induced phosphorylation of the inhibitory subunit of NF{kappa}B (I{kappa}B) [22] and the activation of I{kappa}B kinase by Rho kinase [23]. Relevant to this mechanism, we have preliminary data that show, in BS/GS patients compared with normotensive healthy subjects, an increased expression of I{kappa}B, while NF{kappa}B is unchanged; this is in keeping with a reduced activity of NF{kappa}B (L.A. Calò and E. Pagnin, personal observation).

In conclusion, the overall clinical, biochemical and molecular picture of BS/GS may contribute to an understanding in humans of the pathophysiological mechanisms linking inflammation, hypertension and long-term complication such as cardiovascular remodelling and atherogenesis.

Conflict of interest statement. None declared.

Elisa Pagnin1, Paul A. Davis2, Andrea Semplicini1 and Lorenzo A. Calò1

1 Department of Clinical and Experimental Medicine Clinica Medica 4 University of Padova Italy2 Department of Nutrition University of California Davis, USA

References

  1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685–1695[Free Full Text]
  2. Chae CU, Lee RT, Rifai N, Ridker PM. Blood pressure and inflammation in apparently healthy men. Hypertension 2001; 38: 399–403[Abstract/Free Full Text]
  3. Schillaci G, Pirro M, Gemelli F, et al. Increased C-reactive protein concentrations in never-treated hypertension: the role of systolic and pulse pressures. J Hypertens 2003; 21: 1841–1846[CrossRef][ISI][Medline]
  4. Stumpf C, John S, Jukic J, et al. Enhanced levels of platelet P-selectin and circulating cytokines in young patients with mild arterial hypertension. J Hypertens 2005; 23: 995–1000[ISI][Medline]
  5. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA 2003; 290: 2945–2951[Abstract/Free Full Text]
  6. Niskanen L, Laaksonen DE, Nyyssonen K, et al. Inflammation, abdominal obesity, and smoking as predictors of hypertension. Hypertension 2004; 44: 859–865[Abstract/Free Full Text]
  7. Pauletto P, Rattazzi M. Inflammation and hypertension: the search for a link. Nephrol Dial Transplant 2006; Feb 7 Epub ahead of print; doi:10.1093/ndt/gfl019
  8. Cheng ZJ, Vapaatalo H, Mervaala E. Angiotensin II and vascular inflammation. Med Sci Monit 2005; 11: RA194–RA205[ISI][Medline]
  9. Davis PA, Mussap M, Pagnin E, et al. Early markers of inflammation in a high angiotensin II state. Results of studies in Bartter's/Gitelman's syndromes. Nephrol Dial Transpl 2006; doi:10.1093/ndt/gfl112
  10. Calò LA. Vascular tone control in humans: the utility of studies in Bartter's/Gitelman's syndromes. Kidney Int advance online publication, 15 February 2006; doi:10.1038/sj.ki.5000253
  11. Calò L, Davis PA, Semplicini A. Bartter's/Gitelman's syndrome: a model for the relationships between hypertension, angiotensin II, oxidative stress and remodeling. Clin Nephrol 2003; 59: 393–394[ISI][Medline]
  12. Calò LA, Pagnin E, Davis PA, et al. Increased expression of regulator of G protein signaling–2 (RGS-2) in Bartter's/Gitelman's syndrome. A role in the control of vascular tone and implication for hypertension. J Clin Endocrinol Metab 2004; 89: 4153–4157[Abstract/Free Full Text]
  13. Calò L, Ceolotto G, Milani M, et al. Abnormalities of Gq-mediated cell signaling in Bartter and Gitelman syndromes. Kidney Int 2001; 60: 882–889[CrossRef][ISI][Medline]
  14. Calò L, Davis PA, Semplicini A. Reduced content of alpha subunit of Gq protein in monocytes of Bartter and Gitelman syndromes: relationship with vascular hyporeactivity. Kidney Int 2002; 61: 353–354[ISI][Medline]
  15. Calò LA, Pagnin E, Davis PA, Sartori M, Semplicini A. Oxidative stress-related factors in Bartter's and Gitelman's syndromes: relevance for angiotensin II signalling. Nephrol Dial Transplant 2003; 18: 1518–1525[Abstract/Free Full Text]
  16. Calo L, Sartore G, Bassi A, et al. Reduced susceptibility of low density lipoprotein to oxidation in patients with overproduction of nitric oxide (Bartter's and Gitelman's syndrome). J Hypertens 1998; 16: 1001–1008[CrossRef][ISI][Medline]
  17. Pagnin E, Davis PA, Sartori M, Semplicini A, Pessina AC, Calò LA. Rho kinase and PAI-1 in Bartter's/Gitelman's syndromes: relationship to angiotensin II signaling. J Hypertens 2004; 22: 1963–1969[CrossRef][ISI][Medline]
  18. Pagnin E, Semplicini A, Sartori M, Pessina AC, Calò LA. Reduced mRNA and protein content of Rho guanine nucleotide exchange factor (RhoGEF) in Bartter's and Gitelman's syndromes: relevance for the pathophysiology of hypertension. Am J Hypertens 2005; 18: 1200–1205[CrossRef][ISI][Medline]
  19. Calò L, Davis PA, Milani M, et al. Increased endothelial nitric oxide synthase mRNA level in Bartter's and Gitelman's syndrome. Relationship to vascular reactivity. Clin Nephrol 1999; 51: 12–17[ISI][Medline]
  20. Calò L, D'Angelo A, Cantaro S, et al. Increased urinary NO2–/NO3– and cyclic GMP levels in patients with Bartter's syndrome: relationship to vascular reactivity. Am J Kidney Dis 1996; 27: 874–879
  21. Nakakuki T, Ito M, Iwasaki H, et al. Rho/Rho-kinase pathway contributes to C-reactive protein–induced plasminogen activator inhibitor-1 expression in endothelial cells. Arterioscler Thromb Vasc Biol 2005; 25: 2088–2093[Abstract/Free Full Text]
  22. Perona R, Montaner S, Saniger L, Sanchez-Perez I, Bravo R, Lacal JC. Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev 1997; 11: 463–475[Abstract/Free Full Text]
  23. Segain JP, Raingeard de la Bletiere D, Sauzeau V, et al. Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn's disease and experimental colitis. Gastroenterology 2003; 124: 1180–1187[CrossRef][ISI][Medline]

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