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      Kallikrein/K1, Kinins, and ACE/Kininase II in Homeostasis and in Disease Insight From Human and Experimental Genetic Studies, Therapeutic Implication


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          Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.

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          Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.

          Diabetic nephropathy develops in less than half of all patients with diabetes. To study heredity as a possible risk factor for diabetic kidney disease, we examined the concordance rates for diabetic nephropathy in two sets of families in which both probands and siblings had diabetes mellitus. In one set, the probands (n = 11) had no evidence of diabetic nephropathy, with normal creatinine clearance and a urinary albumin excretion rate below 45 mg per day. In the other set, the probands (n = 26) had undergone kidney transplantation because of diabetic nephropathy. Evidence of nephropathy was found in 2 of the 12 diabetic siblings of the probands without nephropathy (17 percent). Of the 29 diabetic siblings of probands with diabetic nephropathy, 24 (83 percent) had evidence of nephropathy (P less than 0.001), including 12 with end-stage renal disease. No significant differences were noted between the sibling groups with respect to the duration of diabetes, blood pressure, glycemic control, or glycosylated hemoglobin levels. Logistic regression analysis found nephropathy in the proband to be the only factor significantly predictive of the renal status of the diabetic sibling. We conclude that diabetic nephropathy occurs in familial clusters. This is consistent with the hypothesis that heredity helps to determine susceptibility to diabetic nephropathy. However, this study cannot rule out the possible influences of environmental factors shared by siblings.
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            Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

            Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)
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              Endothelium-derived relaxing and contracting factors.

              Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.

                Author and article information

                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                27 June 2019
                : 6
                [1] 1INSERM U1138-CRC , Paris, France
                [2] 2CRC-INSERM U1138, Paris-Descartes University , Paris, France
                [3] 3CRC-INSERM U1138, Sorbonne University , Paris, France
                [4] 4I2MC-INSERM U1048 , Toulouse, France
                Author notes

                Edited by: Sadashiva Karnik, Cleveland Clinic Lerner College of Medicine, United States

                Reviewed by: Coen Maas, University Medical Center Utrecht, Netherlands; Michael Bader, Helmholtz Association of German Research Centers (HZ), Germany

                *Correspondence: Francois Alhenc-Gelas francois.alhenc-gelas@ 123456inserm.fr

                This article was submitted to Hematology, a section of the journal Frontiers in Medicine

                Copyright © 2019 Alhenc-Gelas, Bouby and Girolami.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 123, Pages: 13, Words: 9944
                Funded by: Institut National de la Santé et de la Recherche Médicale 10.13039/501100001677
                Award ID: Paris-Descartes university
                Award ID: Sorbonne University

                angiotensin-converting enzyme,kallikrein (tissue),kinins,vasodilation,genetic human,genetic mouse models,ischemic heart disease,diabetic nephropathy


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