Search

For decades, immunologists have considered the complement system as a paradigm of a proteolytic cascade that, acting cooperatively with the immune system, enhances host defense against infectious organisms. In recent years, advances made in thrombosis research disclosed a functional link between activated neutrophils, monocytes, and platelet-driven thrombogenesis. Forging a physical barrier, the fibrin scaffolds generated by synergism between the extrinsic and intrinsic (contact) pathways of coagulation entrap microbes within microvessels, limiting the systemic spread of infection while enhancing the clearance of pathogens by activated leukocytes. Insight from mice models of thrombosis linked fibrin formation via the intrinsic pathway to the autoactivation of factor XII (FXII) by negatively charged "contact" substances, such as platelet-derived polyphosphates and DNA from neutrophil extracellular traps. Following cleavage by FXIIa, activated plasma kallikrein (PK) initiates inflammation by liberating the nonapeptide bradykinin (BK) from an internal domain of high molecular weight kininogen (HK). Acting as a paracrine mediator, BK induces vasodilation and increases microvascular permeability via activation of endothelial B2R, a constitutively expressed subtype of kinin receptor. During infection, neutrophil-driven extravasation of plasma fuels inflammation via extravascular activation of the kallikrein-kinin system (KKS). Whether liberated by plasma-borne PK, tissue kallikrein, and/or microbial-derived proteases, the short-lived kinins activate immature dendritic cells via B2R, thus linking the infection-associated innate immunity/inflammation to the adaptive arm of immunity. As inflammation persists, a GPI-linked carboxypeptidase M removes the C-terminal arginine from the primary kinin, converting the B2R agonist into a high-affinity ligand for B1R, a GPCR subtype that is transcriptionally upregulated in injured/inflamed tissues. As reviewed here, lessons taken from studies of kinin receptor function in experimental infections have shed light on the complex proteolytic circuits that, acting at the endothelial interface, reciprocally couple immunity to the proinflammatory KKS. [ABSTRACT FROM AUTHOR]

The bradykinin type 2 receptor (B2R), main effector of the pleiotropic kallikrein-kinin system (KKS), has been localized in the key sites related to placentation in human, rat and guinea pig utero-placental units. The present study was directed to characterize the content, the cellular and subcellular localization of B2R in the villi and basal plate of placentas from normal and preeclamptic pregnancies by means of western blotting, immunohistochemistry and immunoelectron microscopy. The protein content of B2R was demonstrated in both placental zones. The villous placenta of normal and preeclamptic pregnancies expressed B2R in syncytiotrophoblast and fetal endothelium; the basal plate displayed B2R in extravillous trophoblasts and decidual cells. Lastly, immunogold electron microscopy revealed B2R in fetal endothelium, syncytiotrophoblast, extravillous cytotrophoblasts and decidual cells; in all cell types the receptor was mainly located in the cytosol and nucleus. The protein content of placental homogenates and the immunoreactivity in the different cells types did not differ between both study groups; however the abundance of nuclear immunogold B2R positive beads in extravillous trophoblasts was greater in the normal than in the preeclamptic placentas. The purpose of describing nuclear B2R in the utero-placental unit, and its increment in normal extravillous trophoblasts, is to stimulate the study of the functional pathways that may be relevant to understand the local role of the B2R in normal and preeclamptic gestation. [ABSTRACT FROM AUTHOR]

The article probes a physiological role of bradykinin (BK) cascade in regulation of epithelial Na+ channel (ENaC) in native tissue, aldosterone-sensitive distal nephron. BK cascade has its own specific role in blunting ENaC activity particularly under conditions of elevated sodium intake. Augmentation of BK signaling in the nephron inhibit ENaC-medicated Na+ reabsorption contributing to the natriuretic and antihypertensive effects of angiotensin-converting enzyme inhibition.

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: The objective of this review is to propose addition of the kallikrein-kinin system (KKS) to the conventional angiogenic repertoire of gestation. This proposal is based on the improved revascularization induced by transfecting the human kallikrein gene; on the angiogenic, chemoattractant, promigratory, antiapoptotic, and antiaggregating effects of bradykinin; and on suppression of these effects by blockade of the bradykinin B2 receptor. In addition, both bradykinin and vascular endothelial growth factor (VEGF) stimulate nitric oxide (NO), and the VEGF and bradykinin receptors have multiple interactions that converge in the endothelial NO synthase (eNOS)-NO pathway. The work of others, and of our group, have demonstrated that eNOS and matrix metalloproteinases, the components of the VEGF and kallikrein-kinin systems, colocalize in specific cell types at human and guinea-pig utero-placental interfaces. Expression of the endothelial angiogenic/vasodilatory repertoire in the syncytiotrophoblast, and in trophoblasts replacing endothelial cells of the spiral arteries, supports the concept that the intervillous space and the transformed uterine arteries represent genuine new vascular structures that should be included in the analysis of pregnancy-induced neovascularization. We believe that the evidence presented provides support for further studies to test the functional significance of the KKS in placental development. [Copyright &y& Elsevier]

The article presents a study which aimed to determine the role of human tissue kallikrein (hK1) in proangiogenic cell (PAC) invasion and its dependency on kinin receptor signaling. The authors discovered new components of the PACs invasive mechanism. KLK1 RNAs when silenced reduces invasive and proangiogenic capacities of PACs while overexpression of Hk1 enhances them. It was also revealed that hK1 coupling to kinin B 2 B receptor (B2R) signaling is essential for the invasive capacity of PACs.

Abstract: The kallikrein–kinin system (KKS) is a system of vasoactive peptides, the kinins, involved in different aspects of remodeling, inflammation and angiogenesis. Kinins mediate their actions through two receptors, B1R and B2R. It is increasingly recognized that the KKS is involved in the inflammatory processes of the heart. Evidence shows that the B2R is beneficial in myocardial diseases, protecting from inflammation, fibrosis and apoptosis, while B1R shows a proinflammatory character contributing to the disease progression by increasing the production of cytokines and stimulating the migration of immune cells. Furthermore, novel important actions of the KKS and its receptors contribute to neovascularization and recruitment of endothelial progenitor cells in ischemic areas and endothelial dysfunction. The kinin receptors could therefore constitute potential therapeutic targets in the treatment of myocardial ischemia and diabetic cardiomyopathy. [Copyright &y& Elsevier]

Abstract: Background: Heart failure (HF) is a clinical syndrome that activates several neurohumoral systems. There is little information on the participation of renal kallikrein-kinin system (KKS) in HF. Kallikreins are key enzymes in this system. Thus it was decided to evaluate the role of renal human tissue kallikrein (hK1) in HF patients and, indirectly, to evaluate the role of renal KKS in this disease. Methods and Results: Twenty-eight systolic HF patients, ≥18 years, in New York Heart Association''s functional classes II-IV, with left ventricular ejection fraction (LVEF) ≤40%, not receiving angiotensin-converting enzyme inhibitors were selected. Twenty-eight healthy individuals, paired according to gender, ethnics and age, were used as controls. Early-morning midstream urine from every subject was used. hK1 amidase activity was estimated with D-Val-Leu-Arg-Nan substrate. Creatinine was determined by Jaffe''s method. hK1 amidase activity was expressed in μM·min−1·mL−1 urine and in μM·min−1·mg−1 creatinine to correct for differences in urine flow rate. hK1 amidase activities were significantly lower in the urine of HF patients. Conclusion: Because the hK1 amidase activity is significantly lower in the urine of systolic HF patients, it can be supposed that the activity of renal KKS may be suppressed in this disease. [Copyright &y& Elsevier]

Abstract: All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischaemia, myocardial infarction and left ventricular hypertrophy, have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular – related diseases. The cardioprotective property of the angiotensin converting enzyme inhibitors is primarily mediated via kinin releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders. [Copyright &y& Elsevier]