Review Article | Published:

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

Nature Clinical Practice Nephrology volume 3, pages 208221 (2007) | Download Citation

Subjects

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

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    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

  8. 8.

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

  9. 9.

    and (2000) Kallikrein and kinin receptor genes. Pharmacol Ther 88: 77–89

  10. 10.

    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

  11. 11.

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

  12. 12.

    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

  13. 13.

    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

  14. 14.

    and (2004) Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 3: 845–852

  15. 15.

    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

  16. 16.

    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

  17. 17.

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

  18. 18.

    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

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

    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

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

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

  28. 28.

    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

  29. 29.

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

  30. 30.

    and (1998) Kinin receptors. Clin Rev Allergy Immunol 16: 385–401

  31. 31.

    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

  32. 32.

    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

  33. 33.

    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

  34. 34.

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

  35. 35.

    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

  36. 36.

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

  37. 37.

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

  38. 38.

    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

  39. 39.

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

  40. 40.

    and (1985) Competitive antagonists of bradykinin. Peptides 6: 161–164

  41. 41.

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

  42. 42.

    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

  43. 43.

    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

  44. 44.

    and (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

  45. 45.

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

  46. 46.

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

  47. 47.

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

  48. 48.

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

  49. 49.

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

  50. 50.

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

  51. 51.

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

  52. 52.

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

  53. 53.

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

  54. 54.

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

  55. 55.

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

  56. 56.

    and (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

  57. 57.

    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

  58. 58.

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

  59. 59.

    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

  60. 60.

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

  61. 61.

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

  62. 62.

    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

  63. 63.

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

  64. 64.

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

  65. 65.

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

  66. 66.

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

  67. 67.

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

  68. 68.

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

  69. 69.

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

  70. 70.

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

  71. 71.

    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

  72. 72.

    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

  73. 73.

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

  74. 74.

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

  75. 75.

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

  76. 76.

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

  77. 77.

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

  78. 78.

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

  79. 79.

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

  80. 80.

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

  81. 81.

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

  82. 82.

    and (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

  83. 83.

    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

  84. 84.

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

  85. 85.

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

  86. 86.

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

  87. 87.

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

  88. 88.

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

  89. 89.

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

  90. 90.

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

  91. 91.

    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

  92. 92.

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

  93. 93.

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

  94. 94.

    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

  95. 95.

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

  96. 96.

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

  97. 97.

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

  98. 98.

    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

  99. 99.

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

  100. 100.

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

  101. 101.

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

  102. 102.

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

  103. 103.

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

  104. 104.

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

  105. 105.

    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

  106. 106.

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

  107. 107.

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

  108. 108.

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

  109. 109.

    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

  110. 110.

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

  111. 111.

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

  112. 112.

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

  113. 113.

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

  114. 114.

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

  115. 115.

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

  116. 116.

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

  117. 117.

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

  118. 118.

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

  119. 119.

    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

  120. 120.

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

  121. 121.

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

  122. 122.

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

  123. 123.

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

  124. 124.

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

  125. 125.

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

  126. 126.

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

  127. 127.

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

  128. 128.

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

  129. 129.

    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

  130. 130.

    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

  131. 131.

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

  132. 132.

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

  133. 133.

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

  134. 134.

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

  135. 135.

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

  136. 136.

    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

  137. 137.

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

  138. 138.

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

  139. 139.

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

  140. 140.

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

  141. 141.

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

  142. 142.

    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

  143. 143.

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

  144. 144.

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

  145. 145.

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

  146. 146.

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

  147. 147.

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

  148. 148.

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

  149. 149.

    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

  150. 150.

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

  151. 151.

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

  152. 152.

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

  153. 153.

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

  154. 154.

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

  155. 155.

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

  156. 156.

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

  157. 157.

    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

  158. 158.

    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

  159. 159.

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

  160. 160.

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

  161. 161.

    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

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

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

    • Samir El-Dahr

Authors

  1. Search for Paolo Madeddu in:

  2. Search for Costanza Emanueli in:

  3. Search for Samir El-Dahr in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paolo Madeddu.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ncpneph0444

Further reading