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Edward P Feener - One of the best experts on this subject based on the ideXlab platform.
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abstract p760 Plasma Kallikrein contributes to intracerebral hemorrhage and hypertension in stroke prone spontaneously hypertensive rats
Stroke, 2021Co-Authors: Fabricio Simao, Allen C Clermont, Jian Guan, Locduyen Pham, Tuna Ustunkaya, Edward P FeenerAbstract:Introduction: Hypertension is a leading risk factor for spontaneous intracerebral hemorrhage. Plasma Kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therap...
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one time intravitreal injection of kvd001 a Plasma Kallikrein inhibitor in patients with central involved diabetic macular edema and reduced vision an open label phase 1b study
Ophthalmology Retina, 2019Co-Authors: Jennifer K Sun, Raj K Maturi, David S Boyer, John A Wells, Victor H Gonzalez, Robert Tansley, Helen Hernandez, Andreas Maetzel, Edward P FeenerAbstract:Abstract Safety of the intravitreal Plasma Kallikrein inhibitor (KVD001) was tested in patients with diabetic macular edema. KVD001 was well tolerated. Systemic absorption was low. Improvement of retinal edema and vision occurred in most study eyes.
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Plasma Kallikrein mediates vascular endothelial growth factor induced retinal dysfunction and thickening
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Allen C Clermont, Michael D Evans, Nivetha Murugesan, Qunfang Zhou, Takeshi Kita, Peter A Robson, Louise J Rushbrooke, Lloyd Paul Aiello, Edward P FeenerAbstract:PURPOSE: Plasma Kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of Plasma Kallikrein in VEGF-induced retinal edema. METHODS: Intravitreal injections of VEGF and saline vehicle were performed in Plasma preKallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective Plasma Kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal Kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy. RESULTS: Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma Kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased Plasma preKallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice. CONCLUSIONS: Vascular endothelial growth factor increases extravasation of Plasma Kallikrein into the retina, and Plasma Kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic Plasma Kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
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abstract wp281 Plasma Kallikrein inhibition reduces tissue plasminogen activator induced stroke damage and hemorrhage transformation
Stroke, 2016Co-Authors: Fabricio Simao, Allen C Clermont, Edward P FeenerAbstract:Introduction and Hypothesis: Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited by serious risk of hemorrhage transformation over time resulting in enhanced brain injury. Plasma Kallikrein (PK) has been implicated in both ischemic and hemorrhagic stroke, however its role during tPA-mediated thrombosis is not yet available. We hypothesized that Plasma Kallikrein inhibition could increase the safety of tPA thrombolysis in stroke. Methods: Male C57Bl6 mice were subjected to middle cerebral artery occlusion (MCAO) by photothrombotic laser, and then treated with tPA (10 mg/kg; via jugular vein) at 2 h in the absence or presence of pretreatment with the selective PK inhibitor BCBPC (1-Benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide) at doses of 1, 3, 10, 20 mg/kg administered for 15 min before tPA. Male PK-deficient (Klkb1-/-) mice were used to further evaluate the role of PK in tPA-induced brain injury following MCAO. Mice were sacrificed at 24 h post-stroke and brains perfused with saline for evaluation of infarct size, edema and cerebral hemorrhage. Western blot was used to evaluate levels and the cleavage of the PK substrate high molecular weight kininogen (HK). Results: Acute tPA administration at 2 hours post MCAO increased infarct volume (2.1 fold), edema (1.8 fold) and hemorrhage transformation (2.7 fold) when compared with the untreated stroke group (p Conclusions: Plasma Kallikrein contributes to the adverse effects of thrombolytic therapy with tPA on infarct volume, edema, and hemorrhagic transformation during ischemic stroke. Co-administration of a Plasma Kallikrein inhibitor with tPA may improve safety and efficacy of thrombolysis.
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased 2 and 11.0-fold (both p r =0.266, p =0.112). Using mass spectrometry-based proteomics we identified 167 vitreous proteins, including 30 that were increased in DME (≥ 4-fold, p p
Allen C Clermont - One of the best experts on this subject based on the ideXlab platform.
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abstract p760 Plasma Kallikrein contributes to intracerebral hemorrhage and hypertension in stroke prone spontaneously hypertensive rats
Stroke, 2021Co-Authors: Fabricio Simao, Allen C Clermont, Jian Guan, Locduyen Pham, Tuna Ustunkaya, Edward P FeenerAbstract:Introduction: Hypertension is a leading risk factor for spontaneous intracerebral hemorrhage. Plasma Kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therap...
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Plasma Kallikrein mediates vascular endothelial growth factor induced retinal dysfunction and thickening
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Allen C Clermont, Michael D Evans, Nivetha Murugesan, Qunfang Zhou, Takeshi Kita, Peter A Robson, Louise J Rushbrooke, Lloyd Paul Aiello, Edward P FeenerAbstract:PURPOSE: Plasma Kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of Plasma Kallikrein in VEGF-induced retinal edema. METHODS: Intravitreal injections of VEGF and saline vehicle were performed in Plasma preKallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective Plasma Kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal Kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy. RESULTS: Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma Kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased Plasma preKallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice. CONCLUSIONS: Vascular endothelial growth factor increases extravasation of Plasma Kallikrein into the retina, and Plasma Kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic Plasma Kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
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abstract wp281 Plasma Kallikrein inhibition reduces tissue plasminogen activator induced stroke damage and hemorrhage transformation
Stroke, 2016Co-Authors: Fabricio Simao, Allen C Clermont, Edward P FeenerAbstract:Introduction and Hypothesis: Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited by serious risk of hemorrhage transformation over time resulting in enhanced brain injury. Plasma Kallikrein (PK) has been implicated in both ischemic and hemorrhagic stroke, however its role during tPA-mediated thrombosis is not yet available. We hypothesized that Plasma Kallikrein inhibition could increase the safety of tPA thrombolysis in stroke. Methods: Male C57Bl6 mice were subjected to middle cerebral artery occlusion (MCAO) by photothrombotic laser, and then treated with tPA (10 mg/kg; via jugular vein) at 2 h in the absence or presence of pretreatment with the selective PK inhibitor BCBPC (1-Benzyl-N-(4-carbamimidoylbenzyl)-1H-pyrazole-4-carboxamide) at doses of 1, 3, 10, 20 mg/kg administered for 15 min before tPA. Male PK-deficient (Klkb1-/-) mice were used to further evaluate the role of PK in tPA-induced brain injury following MCAO. Mice were sacrificed at 24 h post-stroke and brains perfused with saline for evaluation of infarct size, edema and cerebral hemorrhage. Western blot was used to evaluate levels and the cleavage of the PK substrate high molecular weight kininogen (HK). Results: Acute tPA administration at 2 hours post MCAO increased infarct volume (2.1 fold), edema (1.8 fold) and hemorrhage transformation (2.7 fold) when compared with the untreated stroke group (p Conclusions: Plasma Kallikrein contributes to the adverse effects of thrombolytic therapy with tPA on infarct volume, edema, and hemorrhagic transformation during ischemic stroke. Co-administration of a Plasma Kallikrein inhibitor with tPA may improve safety and efficacy of thrombolysis.
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased 2 and 11.0-fold (both p r =0.266, p =0.112). Using mass spectrometry-based proteomics we identified 167 vitreous proteins, including 30 that were increased in DME (≥ 4-fold, p p
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.
A H Schmaier - One of the best experts on this subject based on the ideXlab platform.
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Plasma Kallikrein activates the epithelial sodium channel in vitro but is not essential for volume retention in nephrotic mice
Acta Physiologica, 2018Co-Authors: Silke Haerteis, Anja Schork, Thomas Dorffel, Bernhard N Bohnert, Regina Nacken, Matthias Worn, Mengyun Xiao, Daniel Essigke, Andrea Janessa, A H SchmaierAbstract:AIM Recent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of Plasma Kallikrein (PKLK) as a candidate serine protease in this context. METHODS We analysed PKLK in the urine of patients with chronic kidney disease (CKD, n = 171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK-deficient mice (klkb1-/- ) with experimental nephrotic syndrome induced by doxorubicin injection. RESULTS In patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2 μg mL-1 which was correlated with albuminuria (r = .71) and overhydration as assessed by bioimpedance spectroscopy (r = .44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67 kDa γ-ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in γ-ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome, active PKLK was present in nephrotic urine of klkb1+/+ but not of klkb1-/- mice. However, klkb1-/- mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1+/+ mice. CONCLUSION Plasma Kallikrein is detected in the urine of proteinuric patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice.
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Plasma Kallikrein enhances platelet aggregation response by subthreshold doses of adp
Biochimie, 2017Co-Authors: Tatiana F Ottaiano, Misako U. Sampaio, A H Schmaier, Maria A Juliano, Sheila Siqueira Andrade, Cleide De Oliveira, Mariana Cristina Cabral Silva, Marcus V Buri, Manoel Joao Batista Castello Girao, Alexander WlodawerAbstract:Human Plasma Kallikrein (huPK) potentiates platelet responses to subthreshold doses of ADP, although huPK itself, does not induce platelet aggregation. In the present investigation, we observe that huPK pretreatment of platelets potentiates ADP-induced platelet activation by prior proteolysis of the G-protein-coupled receptor PAR-1. The potentiation of ADP-induced platelet activation by huPK is mediated by the integrin αIIbβ3 through interactions with the KGD/KGE sequence motif in huPK. Integrin αIIbβ3 is a cofactor for huPK binding to platelets to support PAR-1 hydrolysis that contributes to activation of the ADP signaling pathway. This activation pathway leads to phosphorylation of Src, AktS473, ERK1/2, and p38 MAPK, and to Ca2+ release. The effect of huPK is blocked by specific antagonists of PAR-1 (SCH 19197) and αIIbβ3 (abciximab) and by synthetic peptides comprising the KGD and KGE sequence motifs of huPK. Further, recombinant Plasma Kallikrein inhibitor, rBbKI, also blocks this entire mechanism. These results suggest a new function for huPK. Formation of Plasma Kallikrein lowers the threshold for ADP-induced platelet activation. The present observations are consistent with the notion that Plasma Kallikrein promotes vascular disease and thrombosis in the intravascular compartment and its inhibition may ameliorate cardiovascular disease and thrombosis.
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assembly activation and physiologic influence of the Plasma Kallikrein kinin system
International Immunopharmacology, 2008Co-Authors: A H SchmaierAbstract:The Plasma Kallikrein/kinin system that consists of the proteins factor XII, preKallikrein, and high molecular weight kininogen was first recognized as a surface-activated coagulation system arising when blood or Plasma interacts with artificial surfaces. Although surface-activated contact activation occurs in vivo when various negatively charged surfaces become exposed, including a developing platelet thrombus, a physiologic, non-injury mechanism for activation, regulation, and function of this system has been elusive. Recent investigations have shown that there is a physiologic pathway for assembly and activation of this system independent of factor XII. Gene deficient mice of the bradykinin B2 receptor and factor XII have been recognized to have reduced risk for arterial thrombosis. This Plasma proteolytic system influences arterial thrombosis independent of influencing hemostasis. Thus, the Plasma Kallikrein/kinin system has two mechanisms for its activation: one that is dependent and another independent of factor XII. Better understanding of this system may lead to insight into mechanisms for arterial thrombosis, independent of hemostasis.
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the Plasma Kallikrein kinin system its evolution from contact activation
Journal of Thrombosis and Haemostasis, 2007Co-Authors: A H Schmaier, Keith R MccraeAbstract:Summary. The Plasma Kallikrein–kinin system consists of the proteins factor XII (FXII), preKallikrein (PK), and high molecular weight kininogen. It was first recognized as a surface-activated coagulation system that is activated when blood or Plasma interacts with artificial surfaces. Although surface-activated contact activation occurs in vivo in the case of tissue destruction or a developing thrombus, the physiologic basis for the activation and function of this system has not been delineated. New investigations indicate that there is a proteolytic pathway on cells for PK activation independent of FXII. This pathway for PK with subsequent FXII activation indicates physiologic activities. These activities include blood pressure regulation and modulation of thrombosis risk independently of hemostasis. Furthermore, they include regulation of endothelial cell proliferation, angiogenesis and apoptosis through a cellular-based, outside-in signaling system. The present characterizations of this system, which incorrectly had been thought to initiate coagulation, represent an evolution of understanding in this field.
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myeloperoxidase interacts with endothelial cell surface cytokeratin 1 and modulates bradykinin production by the Plasma Kallikrein kinin system
American Journal of Pathology, 2007Co-Authors: Joshua M Astern, A H Schmaier, Fakhri Mahdi, William F Pendergraft, Ronald J Falk, Charles J Jennette, Gloria A PrestonAbstract:During an inflammatory state, functional myeloperoxidase (MPO) is released into the vessel as a result of intravascular neutrophil degradation. One mechanism of resulting cellular injury involves endothelial internalization of MPO, which causes oxidative damage and impairs endothelial signaling. We report the discovery of a protein that facilitates MPO internalization, cytokeratin 1 (CK1), identified using affinity chromatography and mass spectrometry. CK1 interacts with MPO in vitro, even in the presence of 100% human Plasma, thus substantiating biological relevance. Immunofluorescent microscopy confirmed that MPO added to endothelial cells can co-localize with endogenously expressed CK1. CK1 acts as a scaffolding protein for the assembly of the vasoregulatory Plasma Kallikrein-kinin system; thus we explored whether MPO and high molecular weight kininogen (HK) reside on CK1 together or whether they compete for binding. The data support cooperative binding of MPO and HK on cells such that MPO masked the Plasma Kallikrein cleavage site on HK, and MPO-generated oxidants caused inactivation of both HK and Kallikrein. Collectively, interactions between MPO and the components of the Plasma Kallikrein-kinin system resulted in decreased bradykinin production. This study identifies CK1 as a facilitator of MPO-mediated vascular responses and thus provides a new paradigm by which MPO affects vasoregulatory systems.
Qunfang Zhou - One of the best experts on this subject based on the ideXlab platform.
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structure dependent hematological effects of per and polyfluoroalkyl substances on activation of Plasma Kallikrein kinin system cascade
Environmental Science & Technology, 2017Co-Authors: Guangbo Qu, Qunfang Zhou, Yanmin Long, Xingchen Zhao, Aiqian Zhang, Ligang Hu, Guibin JiangAbstract:Per- and polyfluoroalkyl substances (PFASs) are a global concern because of their ubiquitous occurrence and high persistence in human blood, and increasing amounts of unidentified fluorinated compounds are now becoming new exposure issues. This study aims to investigate the structure-related effects of PFASs on the activation of the Plasma Kallikrein-kinin system (KKS). The effects of 20 PFASs and the related long-chain aliphatic compounds were screened, and their binding affinities for the initial zymogen, Hagmen factor XII (FXII) in the KKS, were evaluated by molecular docking analysis. PFASs were demonstrated to activate the KKS in a structure-dependent mode. More specifically, PFASs with longer carbon chain length, higher fluorine atom substitution degree, and terminal acid group exhibited relatively higher activities in activating the KKS. The binding affinities of PFASs with FXII determined their capabilities for inducing KKS activation. The alternative binding modes of PFASs with FXII, together wit...
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Plasma Kallikrein mediates vascular endothelial growth factor induced retinal dysfunction and thickening
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Allen C Clermont, Michael D Evans, Nivetha Murugesan, Qunfang Zhou, Takeshi Kita, Peter A Robson, Louise J Rushbrooke, Lloyd Paul Aiello, Edward P FeenerAbstract:PURPOSE: Plasma Kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of Plasma Kallikrein in VEGF-induced retinal edema. METHODS: Intravitreal injections of VEGF and saline vehicle were performed in Plasma preKallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective Plasma Kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal Kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy. RESULTS: Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma Kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased Plasma preKallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice. CONCLUSIONS: Vascular endothelial growth factor increases extravasation of Plasma Kallikrein into the retina, and Plasma Kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic Plasma Kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased 2 and 11.0-fold (both p r =0.266, p =0.112). Using mass spectrometry-based proteomics we identified 167 vitreous proteins, including 30 that were increased in DME (≥ 4-fold, p p
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.
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role of Plasma Kallikrein in diabetes and metabolism
Thrombosis and Haemostasis, 2013Co-Authors: Edward P Feener, Qunfang Zhou, Ward FickweilerAbstract:Plasma Kallikrein (PK) is a serine protease generated from Plasma preKallikrein, an abundant circulating zymogen expressed by the Klkb1 gene. The physiological actions of PK have been primarily attributed to its production of bradykinin and activation of coagulation factor XII, which promotes inflammation and the intrinsic coagulation pathway. Recent genetic, molecular, and pharmacological studies of PK have provided further insight into its role in physiology and disease. Genetic analyses have revealed common Klkb1 variants that are association with blood metabolite levels, hypertension, and coagulation. Characterisation of animal models with Klkb1 deficiency and PK inhibition have demonstrated effects on inflammation, vascular function, blood pressure regulation, thrombosis, haemostasis, and metabolism. These reports have also identified a host of PK substrates and interactions, which suggest an expanded physiological role for this protease beyond the bradykinin system and coagulation. The review summarises the mechanisms that contribute to PK activation and its emerging role in diabetes and metabolism.
Takeshi Kita - One of the best experts on this subject based on the ideXlab platform.
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Plasma Kallikrein mediates vascular endothelial growth factor induced retinal dysfunction and thickening
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Allen C Clermont, Michael D Evans, Nivetha Murugesan, Qunfang Zhou, Takeshi Kita, Peter A Robson, Louise J Rushbrooke, Lloyd Paul Aiello, Edward P FeenerAbstract:PURPOSE: Plasma Kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of Plasma Kallikrein in VEGF-induced retinal edema. METHODS: Intravitreal injections of VEGF and saline vehicle were performed in Plasma preKallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective Plasma Kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal Kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy. RESULTS: Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma Kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased Plasma preKallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice. CONCLUSIONS: Vascular endothelial growth factor increases extravasation of Plasma Kallikrein into the retina, and Plasma Kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic Plasma Kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased 2 and 11.0-fold (both p r =0.266, p =0.112). Using mass spectrometry-based proteomics we identified 167 vitreous proteins, including 30 that were increased in DME (≥ 4-fold, p p
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Plasma Kallikrein kinin system as a vegf independent mediator of diabetic macular edema
Diabetes, 2015Co-Authors: Takeshi Kita, Allen C Clermont, Nivetha Murugesan, Qunfang Zhou, Lloyd Paul Aiello, Kimihiko Fujisawa, Tatsuro Ishibashi, Edward P FeenerAbstract:This study characterizes the Kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma preKallikrein (PPK) and Plasma Kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.