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.

Mechanisms of Disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling

Nature Clinical Practice Nephrology volume 3, pages 208–221 (2007)Cite this article

Abstract

The pathogenesis of arterial hypertension often involves a rise in systemic vascular resistance (vasoconstriction and vascular remodeling) and impairment of salt excretion in the kidney (inappropriate salt retention despite elevated blood pressure). Experimental and clinical evidence implicate an imbalance between endogenous vasoconstrictor and vasodilator systems in the development and maintenance of hypertension. Kinins (bradykinin and lys-bradykinin) are endogenous vasodilators and natriuretic peptides known best for their ability to antagonize angiotensin-induced vasoconstriction and sodium retention. In humans, angiotensin-converting enzyme inhibitors, a potent class of antihypertensive agents, lower blood pressure at least partially by favoring enhanced kinin accumulation in plasma and target tissues. The beneficial actions of kinins in renal and cardiovascular disease are largely mediated by nitric oxide and prostaglandins, and extend beyond their recognized role in lowering blood pressure to include cardioprotection and nephroprotection. This article is a review of exciting, recently generated genetic, biochemical and clinical data from studies that have examined the importance of the tissue kallikrein–kinin system in protection from hypertension, vascular remodeling and renal fibrosis. Development of novel therapeutic approaches to bolster kinin activity in the vascular wall and in specific compartments in the kidney might be a highly effective strategy for the treatment of hypertension and its complications, including cardiac hypertrophy and renal failure.

Key Points

  • Kinins (bradykinin and lys-bradykinin) are endogenous vasodilators that interact with G-protein-coupled B1 and B2 receptors to antagonize angiotensin-induced vasoconstriction and sodium retention

  • Angiotensin-converting-enzyme inhibitors partially exert their beneficial cardiovascular effects by potentiating endogenous kinins

  • Bradykinin and lys-bradykinin are generated by the kallikrein (kinin-forming enzyme) hK1, which is located in the kidney, and cardiovascular and other tissues

  • The development of antagonists of B1 and B2 receptors and knockout animal models, and genetic association studies, has advanced understanding of the role of the kallikrein–kinin system in hypertension

  • Manipulating expression of components of the kallikrein–kinin system ('gene therapy') has shown promise in hypertensive animal models

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Components of the tissue kallikrein–kinin system
Figure 2: Downstream mechanisms activated by kinins on endothelial cells

References

  1. Bhoola KD et al. (1992) Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 44: 1–80

    CAS  PubMed  Google Scholar 

  2. Nolly H et al. (1990) A kallikrein-like enzyme in blood vessels of one-kidney, one clip hypertensive rats. Hypertension 16: 436–440

    Article  CAS  PubMed  Google Scholar 

  3. Madeddu P et al. (1994) A kallikrein-like enzyme in the aorta of normotensive and hypertensive rats. Hypertension 23: 899–902

    Article  CAS  PubMed  Google Scholar 

  4. Madeddu P et al. (1993) A kallikrein-like enzyme in human vascular tissue. Am J Hypertens 6: 344–348

    Article  CAS  PubMed  Google Scholar 

  5. Kemme M et al. (1999) Identification of immunoreactive tissue prokallikrein on the surface membrane of human neutrophils. Biol Chem 380: 1321–1328

    Article  CAS  PubMed  Google Scholar 

  6. Yayama K et al. (2003) Tissue kallikrein is synthesized and secreted by human vascular endothelial cells. Biochim Biophys Acta 1593: 231–238

    Article  CAS  PubMed  Google Scholar 

  7. Yano Y et al. (2003) Immunohistochemical distributions of the tissue kallikrein-kinin system in ischemic and non-ischemic mouse heart. J Cardiovasc Pharmacol 42 (Suppl 1): S49–S53

    Article  CAS  PubMed  Google Scholar 

  8. Plendl J et al. (2000) Expression of tissue kallikrein and kinin receptors in angiogenic microvascular endothelial cells. Biol Chem 381: 1103–1115

    Article  CAS  PubMed  Google Scholar 

  9. Mahabeer R and Bhoola KD (2000) Kallikrein and kinin receptor genes. Pharmacol Ther 88: 77–89

    Article  CAS  PubMed  Google Scholar 

  10. Chen VC et al. (2000) A positively charged loop on the surface of kallistatin functions to enhance tissue kallikrein inhibition by acting as a secondary binding site for kallikrein. J Biol Chem 275: 40371–40377

    Article  CAS  PubMed  Google Scholar 

  11. Campbell DJ (2001) The kallikrein-kinin system in humans. Clin Exp Pharmacol Physiol 28: 1060–1065

    Article  CAS  PubMed  Google Scholar 

  12. Ura N et al. (1994) The role of kinins and atrial natriuretic peptide on the renal effects of neutral endopeptidase inhibitor in rats. Clin Exp Hypertens 16: 799–808

    Article  CAS  PubMed  Google Scholar 

  13. Hasan AA et al. (1996) Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation. Circulation 94: 517–528

    Article  CAS  PubMed  Google Scholar 

  14. Marceau F and Regoli D (2004) Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 3: 845–852

    Article  CAS  PubMed  Google Scholar 

  15. Leeb-Lundberg LM et al. (2005) International union of pharmacology. XLV: classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 57: 27–77

    Article  CAS  PubMed  Google Scholar 

  16. Fleming I et al. (1995) Calcium signaling in endothelial cells involves activation of tyrosine kinases and leads to activation of mitogen-activated protein kinases. Circ Res 76: 522–529

    Article  CAS  PubMed  Google Scholar 

  17. Fleming I et al. (1996) Interdependence of calcium signaling and protein tyrosine phosphorylation in human endothelial cells. J Biol Chem 271: 11009–11015

    Article  CAS  PubMed  Google Scholar 

  18. Lal MA et al. (1998) A role for PKC epsilon and MAP kinase in bradykinin-induced arachidonic acid release in rabbit CCD cells. Am J Physiol 274: F728–735

    CAS  PubMed  Google Scholar 

  19. Busse R and Fleming I (1995) Regulation and functional consequences of endothelial nitric oxide formation. Ann Med 27: 331–340

    Article  CAS  PubMed  Google Scholar 

  20. Vanhoutte PM et al. (1995) Endothelium-derived relaxing factors and converting enzyme inhibition. Am J Cardiol 76: E3–E12

    Article  Google Scholar 

  21. Harris MB et al. (2001) Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 276: 16587–16591

    Article  CAS  PubMed  Google Scholar 

  22. Emanueli C et al. (2004) Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer. Circulation 110: 1638–1644

    Article  CAS  PubMed  Google Scholar 

  23. Ju H et al. (1998) Inhibitory interactions of the bradykinin B2 receptor with endothelial nitric-oxide synthase. J Biol Chem 273: 24025–24029

    Article  CAS  PubMed  Google Scholar 

  24. Feron O and Balligand JL (2006) Caveolins and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res 69: 788–797

    Article  CAS  PubMed  Google Scholar 

  25. Venema RC (2002) Post-translational mechanisms of endothelial nitric oxide synthase regulation by bradykinin. Int Immunopharmacol 2: 1755–1762

    Article  CAS  PubMed  Google Scholar 

  26. Ignarro LJ et al. (1987) Mechanisms of endothelium-dependent vascular smooth muscle relaxation elicited by bradykinin and VIP. Am J Physiol 253: H1074–H1082

    CAS  PubMed  Google Scholar 

  27. Batenburg WW et al. (2004) Bradykinin-induced relaxation of coronary microarteries: S-nitrosothiols as EDHF? Br J Pharmacol 142: 125–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Taddei S et al. (1999) Vasodilation to bradykinin is mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertensive patients. Circulation 100: 1400–1405

    Article  CAS  PubMed  Google Scholar 

  29. Hecquet C et al. (2000) Human bradykinin B2 receptor is activated by kallikrein and other serine proteases. Mol Pharmacol 58: 828–836

    Article  CAS  PubMed  Google Scholar 

  30. Marceau F and Bachvarov DR (1998) Kinin receptors. Clin Rev Allergy Immunol 16: 385–401

    Article  CAS  PubMed  Google Scholar 

  31. Mathis SA et al. (1996) B1 and B2 kinin receptors mediate distinct patterns of intracellular Ca2+ signaling in single cultured vascular smooth muscle cells. Mol Pharmacol 50: 128–139

    CAS  PubMed  Google Scholar 

  32. Cockcroft JR et al. (1994) Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. Br J Clin Pharmacol 38: 317–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Panza JA et al. (1995) Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation 91: 1732–1738

    Article  CAS  PubMed  Google Scholar 

  34. Groves P et al. (1995) Role of endogenous bradykinin in human coronary vasomotor control. Circulation 92: 3424–3430

    Article  CAS  PubMed  Google Scholar 

  35. Kuga T et al. (1995) Bradykinin-induced vasodilation is impaired at the atherosclerotic site but is preserved at the spastic site of human coronary arteries in vivo. Circulation 92: 183–189

    Article  CAS  PubMed  Google Scholar 

  36. Granger JP and Hall JE (1985) Acute and chronic actions of bradykinin on renal function and arterial pressure. Am J Physiol 248: F87–F92

    CAS  PubMed  Google Scholar 

  37. Campbell DJ et al. (2005) Losartan increases bradykinin levels in hypertensive humans. Circulation 111: 315–320

    Article  CAS  PubMed  Google Scholar 

  38. Madeddu P et al. (1987) The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives. J Hypertens 5: 581–586

    Article  CAS  PubMed  Google Scholar 

  39. Chao J et al. (1997) Kallistatin is a potent new vasodilator. J Clin Invest 100: 11–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vavrek RJ and Stewart JM (1985) Competitive antagonists of bradykinin. Peptides 6: 161–164

    Article  CAS  PubMed  Google Scholar 

  41. Lembeck F et al. (1991) New, long-acting, potent bradykinin antagonists. Br J Pharmacol 102: 297–304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Burgess GM et al. (2000) Bradyzide, a potent non-peptide B2 bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia. Br J Pharmacol 129: 77–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dziadulewicz EK et al. (2000) 1-(2-Nitrophenyl)thiosemicarbazides: a novel class of potent, orally active non-peptide antagonist for the bradykinin B2 receptor. J Med Chem 43: 769–771

    Article  CAS  PubMed  Google Scholar 

  44. Griesbacher T and Legat FJ (1997) Effects of FR173657, a non-peptide B2 antagonist, on kinin-induced hypotension, visceral and peripheral oedema formation and bronchoconstriction. Br J Pharmacol 120: 933–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pruneau D et al. (1999) Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist. Immunopharmacology 43: 187–194

    Article  CAS  PubMed  Google Scholar 

  46. Carbonell LF et al. (1988) Effect of a kinin antagonist on the acute antihypertensive activity of enalaprilat in severe hypertension. Hypertension 11: 239–243

    Article  CAS  PubMed  Google Scholar 

  47. Madeddu P et al. (1995) Early blockade of bradykinin B2-receptors alters the adult cardiovascular phenotype in rats. Hypertension 25: 453–459

    Article  CAS  PubMed  Google Scholar 

  48. Squire IB et al. (2000) Bradykinin B2 receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men. Hypertension 36: 132–136

    Article  CAS  PubMed  Google Scholar 

  49. Madeddu P et al. (1994) Chronic inhibition of bradykinin B2-receptors enhances the slow vasopressor response to angiotensin II. Hypertension 23: 646–652

    Article  CAS  PubMed  Google Scholar 

  50. Madeddu P et al. (1993) Bradykinin B2-receptor blockade facilitates deoxycorticosterone-salt hypertension. Hypertension 21: 980–984

    Article  CAS  PubMed  Google Scholar 

  51. Duka A et al. (2006) Role of bradykinin B1 and B2 receptors in normal blood pressure regulation. Am J Physiol Endocrinol Metab 291: E268–E274

    Article  CAS  PubMed  Google Scholar 

  52. Abadir PM et al. (2006) Angiotensin II type 2 receptor-bradykinin B2 receptor functional heterodimerization. Hypertension 48: 316–322

    Article  CAS  PubMed  Google Scholar 

  53. AbdAlla S et al. (2005) Mesangial AT1/B2 receptor heterodimers contribute to angiotensin II hyperresponsiveness in experimental hypertension. J Mol Neurosci 26: 185–192

    Article  CAS  PubMed  Google Scholar 

  54. Hunt SC et al. (1993) Environmental determinants of urinary kallikrein excretion. Am J Hypertens 6: 226–233

    CAS  PubMed  Google Scholar 

  55. Linz W et al. (1995) Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 47: 25–49

    CAS  PubMed  Google Scholar 

  56. Landmesser U and Drexler H (2006) Effect of angiotensin II type 1 receptor antagonism on endothelial function: role of bradykinin and nitric oxide. J Hypertens 24 (Suppl 1): S39–S43

    Article  CAS  Google Scholar 

  57. Gainer JV et al. (1998) Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 339: 1285–1292

    Article  CAS  PubMed  Google Scholar 

  58. Fenoy FJ et al. (1991) Effect of an angiotensin II and a kinin receptor antagonist on the renal hemodynamic response to captopril. Hypertension 17: 1038–1044

    Article  CAS  PubMed  Google Scholar 

  59. Matsuda H et al. (1999) Zonal heterogeneity in action of angiotensin-converting enzyme inhibitor on renal microcirculation: role of intrarenal bradykinin. J Am Soc Nephrol 10: 2272–2282

    CAS  PubMed  Google Scholar 

  60. Matsuda H et al. (2004) Role of endothelium-derived hyperpolarizing factor in ACE inhibitor-induced renal vasodilation in vivo. Hypertension 43: 603–609

    Article  CAS  PubMed  Google Scholar 

  61. Tornel J et al. (2000) Role of kinins in the control of renal papillary blood flow, pressure natriuresis, and arterial pressure. Circ Res 86: 589–595

    Article  CAS  PubMed  Google Scholar 

  62. Yang XP et al. (2001) Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B2 kinin receptor gene knockout mice. Circ Res 88: 1072–1079

    Article  CAS  PubMed  Google Scholar 

  63. Tschöpe C et al. (2000) Myocardial bradykinin B2-receptor expression at different time points after induction of myocardial infarction. J Hypertens 18: 223–228

    Article  PubMed  Google Scholar 

  64. Tschöpe C et al. (2000) Upregulation of bradykinin B1-receptor expression after myocardial infarction. Br J Pharmacol 129: 1537–1538

    Article  PubMed  PubMed Central  Google Scholar 

  65. Witherow FN et al. (2001) Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Circulation 104: 2177–2181

    Article  CAS  PubMed  Google Scholar 

  66. Davie AP et al. (1999) Role of bradykinin in the vasodilator effects of losartan and enalapril in patients with heart failure. Circulation 100: 268–273

    Article  CAS  PubMed  Google Scholar 

  67. Emanueli C et al. (1998) Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P. Hypertension 31: 1299–1304

    Article  CAS  PubMed  Google Scholar 

  68. Koga N et al. (1993) Anaphylactoid reactions and bradykinin generation in patients treated with LDL-apheresis and an ACE inhibitor. ASAIO J 39: M288–M291

    CAS  PubMed  Google Scholar 

  69. Davidson DC et al. (1994) Prevention with icatibant of anaphylactoid reactions to ACE inhibitor during LDL apheresis. Lancet 343: 1575

    Article  CAS  PubMed  Google Scholar 

  70. Fox AJ et al. (1996) Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat Med 2: 814–817

    Article  CAS  PubMed  Google Scholar 

  71. Molinaro G et al. (2002) Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine9-bradykinin. J Pharmacol Exp Ther 303: 232–237

    Article  CAS  PubMed  Google Scholar 

  72. Pretorius M et al. (2005) A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther 78: 477–485

    Article  CAS  PubMed  Google Scholar 

  73. Madeddu P et al. (1990) Brain kinins are responsible for the pressor effect of intracerebroventricular captopril in spontaneously hypertensive rats. Hypertension 15: 407–412

    Article  CAS  PubMed  Google Scholar 

  74. Emanueli C et al. (1999) The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats. Br J Pharmacol 126: 1769–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Madeddu P et al. (1996) Antisense inhibition of the brain kallikrein-kinin system. Hypertension 28: 980–987

    Article  CAS  PubMed  Google Scholar 

  76. Woodley-Miller C et al. (1989) Restriction fragment length polymorphisms mapped in spontaneously hypertensive rats using kallikrein probes. J Hypertens 7: 865–871

    Article  CAS  PubMed  Google Scholar 

  77. Gavras I and Gavras H (1988) Anti-hormones and blood pressure: bradykinin antagonists in blood pressure regulation. Kidney Int 26 (Suppl): S60–S62

    CAS  Google Scholar 

  78. Madeddu P et al. (1997) Kallikrein-kinin system and blood pressure sensitivity to salt. Hypertension 29: 471–477

    Article  CAS  PubMed  Google Scholar 

  79. Madeddu P et al. (2001) Renal phenotype of low kallikrein rats. Kidney Int 59: 2233–2242

    Article  CAS  PubMed  Google Scholar 

  80. Margolius HS (1998) Tissue kallikreins structure, regulation, and participation in mammalian physiology and disease. Clin Rev Allergy Immunol 16: 337–349

    Article  CAS  PubMed  Google Scholar 

  81. Zinner SH et al. (1978) Stability of blood pressure rank and urinary kallikrein concentration in childhood: an eight-year follow-up. Circulation 58: 908–915

    Article  CAS  PubMed  Google Scholar 

  82. Berge KE and Berg K (1993) No effect of TaqI polymorphism at the human renal kallikrein (KLK1) locus on normal blood pressure level or variability. Clin Genet 44: 196–202

    Article  CAS  PubMed  Google Scholar 

  83. Friend LR et al. (1996) Examination of the role of nitric oxide synthase and renal kallikrein as candidate genes for essential hypertension. Clin Exp Pharmacol Physiol 23: 564–566

    Article  CAS  PubMed  Google Scholar 

  84. Yu H et al. (1998) Identification of human plasma kallikrein gene polymorphisms and evaluation of their role in end-stage renal disease. Hypertension 31: 906–911

    Article  CAS  PubMed  Google Scholar 

  85. Hua H et al. (2005) Relationship between the regulatory region polymorphism of human tissue kallikrein gene and essential hypertension. J Hum Hypertens 19: 715–721

    Article  CAS  PubMed  Google Scholar 

  86. Williams RR et al. (1993) Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. Am J Hypertens 6: S319–S327

    Article  Google Scholar 

  87. Williams RR et al. (1991) Genetic traits related to hypertension and electrolyte metabolism. Hypertension 17 (Suppl 1): S69–S73

    Article  Google Scholar 

  88. Berry TD et al. (1989) A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension 13: 3–8

    Article  CAS  PubMed  Google Scholar 

  89. Slim R et al. (2002) Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J Am Soc Nephrol 13: 968–976

    CAS  PubMed  Google Scholar 

  90. Azizi M et al. (2005) Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans. J Clin Invest 115: 780–787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rossi GP et al. (2006) Tissue kallikrein gene polymorphisms induce no change in endothelium-dependent or independent vasodilation in hypertensive and normotensive subjects. J Hypertens 24: 1955–1963

    Article  CAS  PubMed  Google Scholar 

  92. Majima M et al. (1994) Hypertension induced by a nonpressor dose of angiotensin II in kininogen-deficient rats. Hypertension 24: 111–119

    Article  CAS  PubMed  Google Scholar 

  93. Pravenec M et al. (1991) Cosegregation of blood pressure with a kallikrein gene family polymorphism. Hypertension 17: 242–246

    Article  CAS  PubMed  Google Scholar 

  94. Rigat B et al. (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86: 1343–1346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Danser AH et al. (1995) Angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 92: 1387–1388

    Article  CAS  PubMed  Google Scholar 

  96. Myerson SG et al. (2001) Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan. Circulation 103: 226–230

    Article  CAS  PubMed  Google Scholar 

  97. Rossi GP et al. (2001) Exclusion of the ACE D/I gene polymorphism as a determinant of endothelial dysfunction. Hypertension 37: 293–300

    Article  CAS  PubMed  Google Scholar 

  98. Lung CC et al. (1997) Analysis of an exon 1 polymorphism of the B2 bradykinin receptor gene and its transcript in normal subjects and patients with C1 inhibitor deficiency. J Allergy Clin Immunol 99: 134–146

    CAS  PubMed  Google Scholar 

  99. Brull D et al. (2001) Bradykinin B2BKR receptor polymorphism and left-ventricular growth response. Lancet 358: 1155–1156

    Article  CAS  PubMed  Google Scholar 

  100. Cui J et al. (2005) Sequence variation of bradykinin receptors B1 and B2 and association with hypertension. J Hypertens 23: 55–62

    Article  CAS  PubMed  Google Scholar 

  101. Dhamrait SS et al. (2003) Variation in bradykinin receptor genes increases the cardiovascular risk associated with hypertension. Eur Heart J 24: 1672–1680

    Article  CAS  PubMed  Google Scholar 

  102. Pesquero JB and Bader M (2006) Genetically altered animal models in the kallikrein-kinin system. Biol Chem 387: 119–126

    Article  CAS  PubMed  Google Scholar 

  103. Wang J et al. (1994) Human tissue kallikrein induces hypotension in transgenic mice. Hypertension 23: 236–243

    Article  CAS  PubMed  Google Scholar 

  104. Chao J and Chao L (1996) Functional analysis of human tissue kallikrein in transgenic mouse models. Hypertension 27: 491–494

    Article  CAS  PubMed  Google Scholar 

  105. Silva JA, Jr et al. (2000) Reduced cardiac hypertrophy and altered blood pressure control in transgenic rats with the human tissue kallikrein gene. FASEB J 14: 1858–1860

    Article  CAS  PubMed  Google Scholar 

  106. Wang DZ et al. (1997) Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension 29: 488–493

    Article  CAS  PubMed  Google Scholar 

  107. Pinto YM et al. (2000) Increased kallikrein expression protects against cardiac ischemia. FASEB J 14: 1861–1863

    Article  CAS  PubMed  Google Scholar 

  108. Schanstra JP et al. (2002) In vivo bradykinin B2 receptor activation reduces renal fibrosis. J Clin Invest 110: 371–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tschope C et al. (2004) Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J 18: 828–835

    Article  CAS  PubMed  Google Scholar 

  110. Wang D et al. (2000) Enhanced renal function in bradykinin B2 receptor transgenic mice. Am J Physiol Renal Physiol 278: F484–F491

    Article  CAS  PubMed  Google Scholar 

  111. Meneton P et al. (2001) Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proc Natl Acad Sci USA 98: 2634–2639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Han ED et al. (2002) Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 109: 1057–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bergaya S et al. (2001) Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice. Circ Res 88: 593–599

    Article  CAS  PubMed  Google Scholar 

  114. Hilgers RH et al. (2003) Uterine artery structural and functional changes during pregnancy in tissue kallikrein-deficient mice. Arterioscler Thromb Vasc Biol 23: 1826–1832

    Article  CAS  PubMed  Google Scholar 

  115. Bergaya S et al. (2004) Role of tissue kallikrein in response to flow in mouse resistance arteries. J Hypertens 22: 745–750

    Article  CAS  PubMed  Google Scholar 

  116. Griol-Charhbili V et al. (2005) Role of tissue kallikrein in the cardioprotective effects of ischemic and pharmacological preconditioning in myocardial ischemia. FASEB J 19: 1172–1174

    Article  CAS  PubMed  Google Scholar 

  117. Trabold F et al. (2002) Cardiovascular phenotypes of kinin B2 receptor- and tissue kallikrein-deficient mice. Hypertension 40: 90–95

    Article  CAS  PubMed  Google Scholar 

  118. Krege JH et al. (1997) Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis. Hypertension 29: 150–157

    Article  CAS  PubMed  Google Scholar 

  119. Huang W et al. (2001) Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse. Proc Natl Acad Sci USA 98: 13330–13334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tian B et al. (1997) Blood pressures and cardiovascular homeostasis in mice having reduced or absent angiotensin-converting enzyme gene function. Hypertension 30: 128–133

    Article  CAS  PubMed  Google Scholar 

  121. Xiao HD et al. (2003) Role of bradykinin in angiotensin-converting enzyme knockout mice. Am J Physiol Heart Circ Physiol 284: H1969–H1977

    Article  CAS  PubMed  Google Scholar 

  122. Madeddu P et al. (1997) Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene. Circulation 96: 3570–3578

    Article  CAS  PubMed  Google Scholar 

  123. Duka I et al. (2001) Role of the B2 receptor of bradykinin in insulin sensitivity. Hypertension 38: 1355–1360

    Article  CAS  PubMed  Google Scholar 

  124. Lu B et al. (1997) The control of microvascular permeability and blood pressure by neutral endopeptidase. Nat Med 3: 904–907

    Article  CAS  PubMed  Google Scholar 

  125. Alfie ME et al. (1996) Salt-sensitive hypertension in bradykinin B2 receptor knockout mice. Biochem Biophys Res Commun 224: 625–630

    Article  CAS  PubMed  Google Scholar 

  126. Emanueli C and Madeddu P (1999) Role of the kallikrein-kinin system in the maturation of cardiovascular phenotype. Am J Hypertens 12: 988–999

    Article  CAS  PubMed  Google Scholar 

  127. Maestri R et al. (2003) Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice. Hypertension 41: 1151–1155

    Article  CAS  PubMed  Google Scholar 

  128. Milia AF et al. (2001) Normal blood pressure and renal function in mice lacking the bradykinin B2 receptor. Hypertension 37: 1473–1479

    Article  CAS  PubMed  Google Scholar 

  129. Schanstra JP et al. (2003) Decreased renal NO excretion and reduced glomerular tuft area in mice lacking the bradykinin B2 receptor. Am J Physiol Heart Circ Physiol 284: H1904–H1908

    Article  CAS  PubMed  Google Scholar 

  130. Wang Q et al. (2002) Blood pressure, cardiac, and renal responses to salt and deoxycorticosterone acetate in mice: role of renin genes. J Am Soc Nephrol 13: 1509–1516

    Article  CAS  PubMed  Google Scholar 

  131. Madeddu P et al. (2000) Angiotensin II type 1 receptor blockade prevents cardiac remodeling in bradykinin B2 receptor knockout mice. Hypertension 35: 391–396

    Article  CAS  PubMed  Google Scholar 

  132. Harrison-Bernard LM et al. (2003) Renal segmental microvascular responses to ANG II in AT1A receptor null mice. Am J Physiol Renal Physiol 284: F538–F545

    Article  CAS  PubMed  Google Scholar 

  133. Emanueli C et al. (1998) Enhanced blood pressure sensitivity to deoxycorticosterone in mice with disruption of bradykinin B2 receptor gene. Hypertension 31: 1278–1283

    Article  CAS  PubMed  Google Scholar 

  134. Madeddu P et al. (1998) Renovascular hypertension in bradykinin B2-receptor knockout mice. Hypertension 32: 503–509

    Article  CAS  PubMed  Google Scholar 

  135. Cervenka L et al. (1999) Early onset salt-sensitive hypertension in bradykinin B2 receptor null mice. Hypertension 34: 176–180

    Article  CAS  PubMed  Google Scholar 

  136. Cervenka L et al. (2003) Genetic inactivation of the B2 receptor in mice worsens two-kidney, one-clip hypertension: role of NO and the AT2 receptor. J Hypertens 21: 1531–1538

    Article  CAS  PubMed  Google Scholar 

  137. Xia CF et al. (2006) Postischemic brain injury is exacerbated in mice lacking the kinin B2 receptor. Hypertension 47: 752–761

    Article  CAS  PubMed  Google Scholar 

  138. Shariat-Madar Z et al. (2006) Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin. Blood 108: 192–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pesquero JB et al. (2000) Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc Natl Acad Sci USA 97: 8140–8145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Emanueli C and Madeddu P (2001) Targeting kinin receptors for the treatment of tissue ischaemia. Trends Pharmacol Sci 22: 478–484

    Article  CAS  PubMed  Google Scholar 

  141. Xu J et al. (2005) Role of the B1 kinin receptor in the regulation of cardiac function and remodeling after myocardial infarction. Hypertension 45: 747–753

    Article  CAS  PubMed  Google Scholar 

  142. Bachvarov D et al. (2006) Renal gene expression profiling using kinin B1 and B2 receptor knockout mice reveals comparable modulation of functionally related genes. Biol Chem 387: 15–22

    Article  CAS  PubMed  Google Scholar 

  143. Xiong W et al. (1995) Muscle delivery of human kallikrein gene reduces blood pressure in hypertensive rats. Hypertension 25: 715–719

    Article  CAS  PubMed  Google Scholar 

  144. Wang C et al. (1995) Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. J Clin Invest 95: 1710–1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Jin L et al. (1997) Gene therapy in hypertension: adenovirus-mediated kallikrein gene delivery in hypertensive rats. Hum Gene Ther 8: 1753–1761

    Article  CAS  PubMed  Google Scholar 

  146. Chao J et al. (1998) Adenovirus-mediated kallikrein gene delivery reverses salt-induced renal injury in Dahl salt-sensitive rats. Kidney Int 54: 1250–1260

    Article  CAS  PubMed  Google Scholar 

  147. Yayama K et al. (1998) Kallikrein gene delivery attenuates hypertension and cardiac hypertrophy and enhances renal function in Goldblatt hypertensive rats. Hypertension 31: 1104–1110

    Article  CAS  PubMed  Google Scholar 

  148. Wolf WC et al. (2000) Human tissue kallikrein gene delivery attenuates hypertension, renal injury, and cardiac remodeling in chronic renal failure. Kidney Int 58: 730–739

    Article  CAS  PubMed  Google Scholar 

  149. Zhang JJ et al. (1999) Adenovirus-mediated kallikrein gene delivery reduces aortic thickening and stroke-induced death rate in Dahl salt-sensitive rats. Stroke 30: 1925–1931

    Article  CAS  PubMed  Google Scholar 

  150. Xia CF et al. (2004) Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. Hypertension 43: 452–459

    Article  CAS  PubMed  Google Scholar 

  151. Xia CF et al. (2006) Kallikrein protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. Hum Gene Ther 17: 206–219

    Article  CAS  PubMed  Google Scholar 

  152. Bledsoe G et al. (2006) Reversal of renal fibrosis, inflammation, and glomerular hypertrophy by kallikrein gene delivery. Hum Gene Ther 17: 545–555

    Article  CAS  PubMed  Google Scholar 

  153. Emanueli C et al. (2001) Rescue of impaired angiogenesis in spontaneously hypertensive rats by intramuscular human tissue kallikrein gene transfer. Hypertension 38: 136–141

    Article  CAS  PubMed  Google Scholar 

  154. Spillman F et al. (2006) Regional and global protective effects of tissue kallikrein gene delivery to the peri-infarct myocardium. Regen Med 1: 235–254

    Article  Google Scholar 

  155. Emanueli C et al. (2001) Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation 103: 125–132

    Article  CAS  PubMed  Google Scholar 

  156. Emanueli C et al. (2000) Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol 20: 2379–2385

    Article  CAS  PubMed  Google Scholar 

  157. Emanueli C et al. (2004) Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer. Circulation 110: 1638–1644

    Article  CAS  PubMed  Google Scholar 

  158. Parenti A et al. (2001) The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway. FASEB J 15: 1487–1489

    Article  CAS  PubMed  Google Scholar 

  159. Ebrahimian TG et al. (2005) Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice. Arterioscler Thromb Vasc Biol 25: 65–70

    Article  CAS  PubMed  Google Scholar 

  160. Emanueli C et al. (2002) Angiotensin AT1 receptor signalling modulates reparative angiogenesis induced by limb ischaemia. Br J Pharmacol 135: 87–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Dedio J et al. (2001) Tissue kallikrein KLK1 is expressed de novo in endothelial cells and mediates relaxation of human umbilical veins. Biol Chem 382: 1483–1490

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the British Heart Foundation project grant number PG/06/035/20641 (“New insights into the mechanisms of kallikrein-induced neovascularisation”) to P Madeddu. The Chair of Experimental Cardiovascular Medicine is associated with the European Vascular Genomic Network of Excellence (EVGN).

Author information

Authors and Affiliations

  1. P Madeddu is Chair of Experimental Cardiovascular Medicine, and C Emanueli is the British Heart Foundation Senior Lecturer of Experimental Cardiovascular Medicine, at Bristol Heart Institute, Bristol University, Bristol, UK.,

    Paolo Madeddu & Costanza Emanueli

  2. P Madeddu is also Project Leader at Multimedica IRCCS, Milan, Italy.,

    Paolo Madeddu

  3. Department of Pediatrics, S El-Dahr is Professor and Chief of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, LA, USA.,

    Samir El-Dahr

Authors
  1. Paolo Madeddu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Costanza Emanueli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samir El-Dahr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Madeddu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Madeddu, P., Emanueli, C. & El-Dahr, S. Mechanisms of Disease: the tissue kallikrein–kinin system in hypertension and vascular remodeling. Nat Rev Nephrol 3, 208–221 (2007). https://doi.org/10.1038/ncpneph0444

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneph0444

This article is cited by

Search

Advanced 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