Skip to main content

Advertisement

SpringerLink
Log in

Mechanistic approach to the pathophysiology of target organ damage in hypertension from studies in a human model with characteristics opposite to hypertension: Bartter’s and Gitelman’s syndromes

  • Short Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Introduction

Extensive studies using Bartter’s/Gitelman’s syndrome patients have provided insights into the angiotensin II (Ang II) signaling pathways involved in the regulation of vascular tone and cardiovascular–renal remodeling. The renin–angiotensin–aldosterone system is activated in these syndromes, however, patients do not develop hypertension and cardiovascular remodeling and clinically manifest conditions opposite to hypertension. The short- and the long-term signaling of Ang II remains an important matter of investigation to shed light on mechanisms responsible for the pathophysiology of hypertension and its long-term complications. The long-term signaling of Ang II is involved in the pathophysiology of cardiovascular–renal remodeling and inflammatory responses in which the balance between RhoA/Rho kinase pathway and NO system plays a crucial role.

Methods and results

In this brief review, the results of our studies in Bartter’s and Gitelman’s syndromes are reported on these processes.

Conclusions

The information obtained from these studies can clarify, confirm or be used to extend the biochemical mechanisms responsible for the pathophysiology of hypertension and its long-term complications and could offer further chances to identify additional potential significant targets of therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G (2009) Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119:524–530

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D (2004) Bartter’s and Gitelman’s syndromes: from gene to clinic. Nephron Physiol 96:65–78

    Article  Google Scholar 

  3. Calò L, D’Angelo A, Cantaro S, Rizzolo M, Favaro S, Antonello A, Borsatti A (1996) Intracellular calcium signalling and vascular reactivity in Bartter’s syndrome. Nephron 72:570–573

    Article  PubMed  Google Scholar 

  4. Calò LA, Schiavo S, Davis PA, Pagnin E, Mormino P, D’Angelo A, Pessina AC (2010) Angiotensin II signaling via type 2 receptors in a human model of vascular hyporeactivity: implications for hypertension. J Hypertens 28:111–118

    Article  PubMed  Google Scholar 

  5. Calò LA (2006) Vascular tone control in humans: insights from studies in Bartter’s/Gitelman’s syndromes. Kidney Int 69:963–966

    Article  PubMed  Google Scholar 

  6. Calò LA, Davis PA, Rossi GP (2014) Understanding the mechanisms of angiotensin II signaling involved in hypertension and its long-term sequelae: insights from Bartter’s and Gitelman’s syndromes, human models of endogenous angiotensin II signaling antagonism. J Hypertens 32:2109–2119

    Article  PubMed  Google Scholar 

  7. Calò LA, Ceolotto G, Milani M, Pagnin E, van den Heuvel LP, Sartori M, Davis PA, Costa R, Semplicini A (2001) Abnormalities of Gq-mediated cell signaling in Bartter and Gitelman syndromes. Kidney Int 60:882–889

    Article  PubMed  Google Scholar 

  8. Calò LA, Pagnin E, Davis PA, Sartori M, Ceolotto G, Pessina AC, Semplicini A (2004) 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 89:4153–4157

    Article  PubMed  Google Scholar 

  9. Calò LA, Pagnin E, Ceolotto G, Davis PA, Schiavo S, Papparella I, Semplicini A, Pessina AC (2008) Silencing regulator of G protein signaling-2 (RGS-2) increases angiotensin II signaling: insights into hypertension from findings in Bartter’s/Gitelman’s syndromes. J Hypertens 26:938–945

    Article  PubMed  Google Scholar 

  10. Di Virgilio F, Calò L, Cantaro S, Favaro S, Piccoli A, Borsatti A (1987) Resting and stimulated cytosolic free calcium levels in neutrophils from patients with Bartter’s syndrome. Clin Sci 72:483–488

    CAS  PubMed  Google Scholar 

  11. Calò L, D’Angelo A, Cantaro S, Rizzolo M, Favaro S, Antonello A, Borsatti A (1996) Intracellular calcium signalling and vascular reactivity in Bartter’s syndrome. Nephron 72:570–573

    Article  PubMed  Google Scholar 

  12. Mehta PK, Griendling KK (2007) Angiotensin II cell signaling. Physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 92:C82–C97

    Google Scholar 

  13. Griendling KK, FitzGerald GA (2003) Oxidative stress and cardiovascular injury: part II: animal and human studies. Circulation 108:2034–2040

    Article  PubMed  Google Scholar 

  14. Calò LA, Pagnin E, Davis PA, Sartori M, Semplicini A (2003) Oxidative stress related factors in Bartter’s and Gitelman’s sindrome: relevance for angiotensin II signaling. Nephrol Dial Transplant 18:1518–1525

    Article  PubMed  Google Scholar 

  15. Calò LA, Facco M, Davis PA, Pagnin E, Maso LD, Puato M, Caielli P, Agostini C, Pessina AC (2011) Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling. Hypertens Res 34:1017–1022

    Article  PubMed  Google Scholar 

  16. Calò LA, Sartore G, Bassi A, Basso C, Bertocco S, Marin R, Zambon S, Cantaro S, D’Angelo A, Davis PA, Manzato E, Crepaldi G (1998) Reduced susceptibility of low density lipoprotein to oxidation in patients with overproduction of nitric oxide (Bartter’s and Gitelman’s sindrome). J Hypertens 16:1001–1008

    Article  PubMed  Google Scholar 

  17. Calò L, Davis PA, Milani M, Cantaro S, Antonello A, Favaro S, D’Angelo A (1999) Increased endothelial nitric oxide synthase mRNA level in Bartter’s and Gitelman’s syndrome. Relationship to vascular reactivity. Clin Nephrol 51:12–17

    PubMed  Google Scholar 

  18. Calò L, D’Angelo A, Cantaro S, Bordin MC, Favaro S, Antonello A, Borsatti A (1996) Increased urinary NO2-/NO3- and cyclic GMP levels in patients with Bartter’s syndrome: relationship to vascular reactivity. Am J Kidney Dis 27:874–879

    Article  Google Scholar 

  19. Calò LA, Puato M, Schiavo S, Zanardo M, Tirrito C, Pagnin E, Balbi G, Davis PA, Palatini P, Pauletto P (2008) Absence of vascular remodelling in a high angiotensin-II state (Bartter’s and Gitelman’s syndromes): implications for angiotensin II signalling pathways. Nephrol Dial Transplant 23:2804–2809

    Article  PubMed  Google Scholar 

  20. Pagnin E, Davis PA, Sartori M, Semplicini A, Pessina AC, Calò LA (2004) Rho kinase and PAI-1 in Bartter’s/Gitelman’s syndromes: relationship to angiotensin II signaling. J Hypertens 22:1963–1969

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  22. Loirand G, Guerin P, Pacaud P (2006) Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 98:322–324

    Article  CAS  PubMed  Google Scholar 

  23. Sauzeau V, Rolli-Derkinderen M, Marionneau C, Loirand G, Pacaud P (2003) RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activation. J Biol Chem 278:9472–9480

    Article  CAS  PubMed  Google Scholar 

  24. Jin HG, Yamashita H, Nagano Y, Fukuba H, Hiji M, Ohtsuki T, Takahashi T, Kohriyama T, Kaibuchi K, Matsumoto M (2006) Hypoxia-induced upregulation of endothelial small G protein RhoA and Rho-kinase/ROCK2 inhibits eNOS expression. Neurosci Lett 408:62–67

    Article  CAS  PubMed  Google Scholar 

  25. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, Ichiki T, Takahashi S, Takeshita A (2003) Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo. Effect on endothelial NAD(P)H oxidase system. Circ Res 93:767–775

    Article  CAS  PubMed  Google Scholar 

  26. Kataoka C, Egashira K, Inoue S, Takemoto M, Ni W, Koyanagi M, Kitamoto S, Usui M, Kaibuchi K, Shimokawa H, Takeshita A (2002) Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 39:245–250

    Article  CAS  PubMed  Google Scholar 

  27. Pagnin E, Davis PA, Semplicini A, Calò LA (2006) The search for a link between inflammation and hypertension—contribution from Bartter’s/Gitelman’s syndromes. Nephrol Dial Transplant 21:2340–2342

    Article  PubMed  Google Scholar 

  28. Sowers JR (2004) Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol 286:H1597–H1602

    Article  CAS  PubMed  Google Scholar 

  29. Nakakuki T, Ito M, Iwasaki H, Kureishi Y, Okamoto R, Moriki N, Kongo M, Kato S, Yamada N, Isaka N, Nakano T (2005) Rho/Rho-kinase pathway contributes to C-reactive protein-induced plasminogen activator inhibitor-1 expression in endothelial cells. Arterioscler Thromb Vasc Biol 25:2088–2093

    Article  CAS  PubMed  Google Scholar 

  30. Wolfrum S, Dendorfer A, Rikitake Y, Stalker TJ, Gong Y, Scalia R, Dominiak P, Liao JK (2004) Inhibition of Rhokinase leads to rapid activation of phosphatidylinositol 3 kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 24:1842–1847

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Wennerberg K, Der CJ (2004) Rho-family GTPases: it’s not only Rac and Rho (and I like it). J Cell Sci 117:1301–1312

    Article  CAS  PubMed  Google Scholar 

  32. Siderovski DP, Willard FS (2005) The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. Int J Biol Sci 1:51–66

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Ying Z, Jin L, Dorrance AM, Webb RC (2004) Increased expression of mRNA for regulator of G protein signaling domain-containing Rho guanine nucleotide exchange factors in aorta from stroke-prone spontaneously hypertensive rats. Am J Hypertens 17:981–985

    Article  CAS  PubMed  Google Scholar 

  34. Wuertz MC, Lorincz A, Vettel C, Thomas MA, Wieland T, Lutz S (2010) p63RhoGEF—a key mediator of angiotensin II dependent signaling and processes in vascular smooth muscle cells. FASEB J 24:4865–4876

    Article  CAS  PubMed  Google Scholar 

  35. Momotani K, Artamonov MV, Utepbergenov D, Derewenda U, Derewenda ZS, Somlyo AV (2011) p63RhoGEF couples Gaq/11-mediated signaling to Ca2+sensitization of vascular smooth muscle contractility. Circ Res 109:993–1002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G (2010) The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med 16:183–190

    Article  CAS  PubMed  Google Scholar 

  37. Calò LA, Davis PA, Pagnin E, Dal Maso L, Maiolino G, Seccia TM, Pessina AC, Rossi GP (2014) Increased level of p63RhoGEF and RhoA/Rho kinase activity in hypertensive patients. Implications for vascular tone regulation and cardiovascular remodeling. J Hypertens 32:331–338

    Article  PubMed  Google Scholar 

  38. Calò LA, Pagnin E, Davis PA, Sartori M, Semplicini A, Pessina AC (2005) Rho kinase inhibition and vascular protection: support from studies in Bartter and Gitelman syndrome. Arterioscler Thromb Vasc Biol 25:34–35

    Article  Google Scholar 

  39. Pagnin E, Semplicini A, Sartori M, Pessina AC, Calò LA (2005) 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 18:1200–1205

    Article  CAS  PubMed  Google Scholar 

  40. Wirth A (2010) Rho kinase and hypertension. Biochim Biophys Acta 1802:1276–1284

    Article  CAS  PubMed  Google Scholar 

  41. Savoia C, Tabet F, Yao G, Schiffrin EL, Touyz RM (2005) Negative regulation of RhoA/Rho kinase by angiotensin II type 2 receptor in vascular smooth muscle cells: role in angiotensin II-induced vasodilation in stroke-prone spontaneously hypertensive rats. J Hypertens 23:1037–1045

    Article  CAS  PubMed  Google Scholar 

  42. Calò LA, Montisci R, Scognamiglio R, Davis PA, Pagnin E, Schiavo S, Mormino P, Semplicini A, Palatini P, D’Angelo A, Pessina AC (2009) High angiotensin II state without cardiac remodeling (Bartter’s and Gitelman’s syndromes). Are angiotensin II type 2 receptors involved? J Endocrinol Invest 32:832–836

    Article  PubMed  Google Scholar 

  43. Carey RM (2005) Cardiovascular and renal regulation by the angiotensin type 2 receptor: the AT2 receptor comes of age. Hypertension 45:840–844

    Article  CAS  PubMed  Google Scholar 

  44. Davis PA, Mussap M, Pagnin E, Bertipaglia L, Savica V, Semplicini A, Calò LA (2006) Early markers of inflammation in a high angiotensin II state. Results of studies in Bartter’s/Gitelman’s syndromes. Nephrol Dial Transplant 21:1697–1701

    Article  CAS  PubMed  Google Scholar 

  45. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J (2002) Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int 62(Suppl. 82):12–22

    Article  Google Scholar 

  46. Cheng ZJ, Vapaatalo H, Mervaala E (2005) Angiotensin II and vascular inflammation. Med Sci Monit 11:RA194–RA205

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  48. Nakakuki T, Ito M, Iwasaki H, Kureishi Y, Okamoto R, Moriki N, Kongo M, Kato S, Yamada N, Isaka N, Nakano T (2005) Rho/Rho-kinase pathway contributes to C-reactive protein-induced plasminogen activator inhibitor-1 expression in endothelial cells. Arterioscler Thromb Vasc Biol 25:2088–2093

    Article  CAS  PubMed  Google Scholar 

  49. Segain JP, Raingeard de la Bletiere D, Sauzeau V, Bourreille A, Hilaret G, Cario-Toumaniantz C, Pacaud P, Galmiche JP, Loirand G (2003) Rho kinase blockade prevents inflammation via nuclear factor kappa B inhibition: evidence in Crohn’s disease and experimental colitis. Gastroenterology 124:1180–1187

    Article  CAS  PubMed  Google Scholar 

  50. Calò LA, Davis PA, Pagnin E, Schiavo S, Semplicini A, Pessina AC (2008) Linking inflammation and hypertension in humans: studies in Bartter’s/Gitelman’s syndromes. J Hum Hypertens 22:223–225

    Article  PubMed  Google Scholar 

  51. Shi J, Wei L (2013) Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol 62:341–354

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

No informed consent.

Author information

Authors and Affiliations

  1. Department of Medicine, Nephrology and Hypertension, University of Padova, Via Giustiniani, 2, 35128, Padua, Italy

    L. A. Calò & G. Maiolino

Authors
  1. L. A. Calò
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Maiolino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. A. Calò.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calò, L.A., Maiolino, G. Mechanistic approach to the pathophysiology of target organ damage in hypertension from studies in a human model with characteristics opposite to hypertension: Bartter’s and Gitelman’s syndromes. J Endocrinol Invest 38, 711–716 (2015). https://doi.org/10.1007/s40618-015-0249-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-015-0249-z

Keywords

Search

Navigation