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

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

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

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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).

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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

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