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NDT Advance Access originally published online on November 15, 2005
Nephrology Dialysis Transplantation 2006 21(4):1131-1132; doi:10.1093/ndt/gfi272
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Letter

Rho/Rho-kinase and C-reactive protein relationship in hypertension and atherosclerosis

Email: renzcalo{at}unipd.it

Sir,

RhoA/Rho kinase pathway has been advanced in the pathogenesis of hypertension and atherosclerosis [1]. This is based on its modulation of regulatory chain phosphorylation of myosin II which contributes to smooth muscle Ca2+ sensitization [2], increased expression of NAD(P)H oxidase [3] and induction of oxidative stress. In addition, Rho kinase activation regulates endothelial nitric oxide synthase [4] and also controls the production of the profibrotic plasminogen activator inhibitor-1 (PAI-1) [5] and inhibition of Rho kinase results in the suppression of neointimal formation [6], activation of Akt pathway and eNOS [7], further confirming an important role of Rho/Rho kinase inhibition for cardiovascular protection and prevention of atherogenesis.

Evidence has been recently provided for the involvement of Rho/Rho-kinase signaling in C Reactive Protein (CRP)-induced atherothrombogenesis. CRP has been shown, in fact, to activate Rho/Rho-kinase signaling, which through activation of NF{kappa}B activity results in PAI-1 expression, known atherothrombogenic factor. This suggests Rho/Rho-kinase inhibition as a potential therapeutic strategy for the prevention of atherogenesis [8].

The recent results from our ongoing studies in patients with Bartter's and Gitelman's syndrome (BS/GS) [9,10] provide additional support as well as additional evidence for the importance of Rho/Rho kinase signaling–CRP relationship in atherothrombogenesis. Of direct relevance is our recent demonstration in BS/GS patients that RhoA/Rho kinase pathway is blunted as shown by the reduced gene and protein expression and response to angiotensin II (Ang II) challenge of Rho kinase and PAI-1 [11], and by the reduced gene and protein expression of the upstream regulator of RhoA, p115RhoGEF [12]. BS/GS, caused by gene defects in specific kidney transporters and ion channels, presents 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 [9,10]. BS/GS has been considered a good human model to explore the mechanisms responsible for maintenance/controlling vascular tone and vascular remodeling [10,13]. In fact, understanding why patients with BS/GS do not develop hypertension and its complications such as cardiovascular remodeling 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 signaling pathway is blunted as documented by the increased regulator of G-protein signaling-2 [14] reduced G{alpha}q gene and protein expression [15,16] and reduced related downstream cellular events such as intracellular Ca2+ and IP3 release, and PKC activity [15,17,18]. The long-term signaling pathway of Ang II, which modulates the cell redox state to promote cardiovascular remodeling and atherosclerosis, is also altered in BS/GS [19,20]. The reduced peripheral resistance, vascular hyporeactivity, and normohypotension typical of BS/GS patients and their collection of biochemical characteristics present, therefore, a mirror image of those found in hypertension. The downregulation of Rho/Rho kinase pathway noted in our recent studies occurred in the context of the increased level of the endothelial subunit of NO synthase (eNOS) mRNA [21] alongside elevated urinary NO metabolites and cGMP levels [22], which parallels in humans the upregulation of the NO system upon Rho kinase inhibition recently shown in vitro in endothelial cells [7] and in vivo in Dahl rats [23]. More importantly, we have very recently found in BS/GS patients compared with normotensive healthy subjects, unchanged CRP plasma level as well as acute phase reactants such as serum amyloid A, VCAM and ICAM, and inflammatory process related cytokines such as interleukin 6 and TNF{alpha} [24]. The BS/GS patients’ unchanged level of CPR [24] together with their downregulated Rho/Rho kinase pathway [11,12], reduced PAI-1 gene and protein expression [11] and unchanged plasma level of the inflammatory cytokines interleukin 6 and TNF{alpha} [24], whose expression is known to be dependent on NF{kappa}B activity, also provide in a human model of altered vascular tone regulation, confirmatory data in support of those derived from in vitro studies [8]. In addition, our findings in BS/GS could also shed some light on the molecular mechanisms involved in CRP-induced gene expression. One possible mechanism for the CRP-induced gene expression is, in fact, the activation of NF{kappa}B through the RhoA induced phosphorylation of the inhibitory subunit I{kappa}B [25] and the activation of I{kappa}B kinase by Rho kinase [26]. Relevant to this mechanism, we have preliminary data that, instead, show in BS/GS patients compared with normotensive healthy subjects, an increased expression of I{kappa}B while NF{kappa}B is unchanged, which is in keeping with a reduced activity of NF{kappa}B (Calò LA and Pagnin E, personal observation).

In conclusion, the overall clinical, biochemical and molecular picture of BS/GS may contribute to an understanding in humans of the molecular mechanism of CRP/Rho/Rho kinase/Nf{kappa}B relationship that determines the involvement of CRP in atherothrombogenesis demonstrated in vitro [8] and thus confirming the utility of Rho/Rho kinase inhibition for cardiovascular protection in humans.

Conflict of interest statement. None declared.

Lorenzo A. Calò1, Elisa Pagnin1, Michele Mussap2, Paul A. Davis3 and Andrea Semplicini1

1 Department of Clinical and Experimental Medicine Clinica Medica 42 Laboratory Medicine University of Padova Italy3 Department of Nutrition University of California Davis USA

References

  1. Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension 2001; 38: 1307–1310[Abstract/Free Full Text]
  2. Wettschureck N, Offermanns S. Rho/Rho-kinase mediated signaling in physiology and pathophysiology. J Mol Med 2002; 80: 629–638[CrossRef][Web of Science][Medline]
  3. Higashi M, Hiroki J, Hattori T et al. Long-term inhibition of Rhokinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res 2003; 93: 767–775[Abstract/Free Full Text]
  4. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 2002; 106: 57–62[Abstract/Free Full Text]
  5. Takeda K, Ichiki T, Tokunou T et al. Critical role of Rho-kinase and MEK-ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. Arterioscler Thromb Vasc Biol 2001; 21: 868–873[Abstract/Free Full Text]
  6. Eto Y, Shimokawa H, Hiroki J et al. Gene transfer of dominant negative Rho kinase suppresses neointimal formation after balloon injury in pigs. Am J Physiol 2000; 278: H1744–H1750[Web of Science]
  7. Wolfrum S, Dendorfer A, Rikitake Y et al. Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3 kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 2004; 24: 1842–1847[Abstract/Free Full Text]
  8. 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]
  9. Calò L, Davis PA, Semplicini A. Regulation of vascular tone in Bartter's and Gitelman's syndromes. Crit Rev Clin Lab Sci 2000; 37: 503–523[CrossRef][Web of Science][Medline]
  10. Calò 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[CrossRef]
  11. 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][Web of Science][Medline]
  12. 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][Web of Science][Medline]
  13. 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[Web of Science][Medline]
  14. 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]
  15. 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][Web of Science][Medline]
  16. 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[Web of Science][Medline]
  17. Di Virgilio F, Calò L, Cantaro S, Favaro S, Piccoli A, Borsatti A. Resting and stimulated cytosolic free calcium levels in neutrophils from patients with Bartter's syndrome. Clin Sci 1987; 72: 483–488[Medline]
  18. Calo L, D’Angelo A, Cantaro S et al. Intracellular calcium signalling and vascular reactivity in Bartter's syndrome. Nephron 1996; 72: 570–573[Medline]
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  20. Calò 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][Web of Science][Medline]
  21. 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[Web of Science][Medline]
  22. 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
  23. Mita S, Kobayashi N, Yoshida K, Nakano S, Matsuoka H. Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. J Hypertens 2005; 23: 87–96[CrossRef][Web of Science][Medline]
  24. Davis PA, Mussap M, Pagnin E, Bertipaglia L, Semplicini A, Calò LA. Early markers of inflammation in a high angiotensin II state. Results of studies in Bartter's/Gitelman's syndromes. J Intern Med 2005 submitted
  25. 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]
  26. 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][Web of Science][Medline]

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