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Julie Chao - One of the best experts on this subject based on the ideXlab platform.
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Tissue Kallikrein-kinin therapy in hypertension and organ damage.
Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques, 2014Co-Authors: Julie Chao, Grant Bledsoe, Lee ChaoAbstract:Tissue Kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, Tissue Kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and γ-epithelial Na channel. The Tissue Kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue Kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment Tissue Kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.
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Tissue Kallikrein Activation of the Epithelial Na Channel
American Journal of Physiology-renal Physiology, 2012Co-Authors: Ankit B Patel, Julie Chao, Lawrence G PalmerAbstract:Epithelial Na Channels (ENaC) are responsible for the apical entry of Na+ in a number of different epithelia including the renal connecting tubule and cortical collecting duct. Proteolytic cleavage of γ-ENaC by serine proteases, including trypsin, furin, elastase, and prostasin, has been shown to increase channel activity. Here, we investigate the ability of another serine protease, Tissue Kallikrein, to regulate ENaC. We show that excretion of Tissue Kallikrein, which is secreted into the lumen of the connecting tubule, is stimulated following 5 days of a high-K+ or low-Na+ diet in rats. Urinary proteins reconstituted in a low-Na buffer activated amiloride-sensitive currents (INa) in ENaC-expressing oocytes, suggesting an endogenous urinary protease can activate ENaC. We next tested whether Tissue Kallikrein can directly cleave and activate ENaC. When rat ENaC-expressing oocytes were exposed to purified Tissue Kallikrein from rat urine (RTK), ENaC currents increased threefold in both the presence and abs...
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Tissue Kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing.
Biological chemistry, 2010Co-Authors: Julie Chao, Grant Bledsoe, Bo Shen, Lin Gao, Chun-fang Xia, Lee ChaoAbstract:Tissue Kallikrein (KLK1) processes low-molecular weight kininogen to produce vasoactive kinins, which exert biological functions via kinin receptor signaling. Using various delivery approaches, we have demonstrated that Tissue Kallikrein through kinin B2 receptor signaling exhibits a wide spectrum of beneficial effects by reducing cardiac and renal injuries, restenosis and ischemic stroke, and by promoting angiogenesis and skin wound healing, independent of blood pressure reduction. Protection by Tissue Kallikrein in oxidative organ damage is attributed to the inhibition of apoptosis, inflammation, hypertrophy and fibrosis. Tissue Kallikrein also enhances neovascularization in ischemic heart and limb. Moreover, Tissue Kallikrein/kinin infusion not only prevents but also reverses kidney injury, inflammation and fibrosis in salt-induced hypertensive rats. Furthermore, there is a wide time window for Kallikrein administration in protection against ischemic brain infarction, as delayed Kallikrein infusion for 24 h after cerebral ischemia in rats is effective in reducing neurological deficits, infarct size, apoptosis and inflammation. Importantly, in the clinical setting, human Tissue Kallikrein has been proven to be effective in the treatment of patients with acute brain infarction when injected within 48 h after stroke onset. Finally, Kallikrein promotes skin wound healing and keratinocyte migration by direct activation of protease-activated receptor 1.
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Tissue Kallikrein promotes neovascularization and improves cardiac function by the akt glycogen synthase kinase 3β pathway
Cardiovascular Research, 2008Co-Authors: Lee Chao, Bo Shen, Lin Gao, Yuyu Yao, Hang Yin, Robert S Smith, Yuying Liu, Julie ChaoAbstract:Aims We investigated the role of the Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of Tissue Kallikrein on myocardial injury by promoting angiogenesis and blood flow in rats after myocardial infarction (MI). Methods and results Human Tissue Kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3β (Ad.GSK-3βS9A), was injected into rat myocardium after MI. The expression of recombinant human Kallikrein in rat heart significantly improved cardiac function and reduced infarct size 10 days after gene delivery. Kallikrein administration significantly increased myocardial blood flow as well as capillary and arteriole densities in the infarcted myocardium. Kallikrein increased cardiac Akt and GSK-3β phosphorylation in conjunction with decreased GSK-3β activity and the upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). All of Kallikrein’s effects on the myocardium were abrogated by Ad.DN-Akt and Ad.GSK-3βS9A. Moreover, in cultured human aortic endothelial cells, Tissue Kallikrein stimulated capillary tube formation and promoted cell migration; however, these effects were blocked by Ad.DN-Akt, Ad.GSK-3βS9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, Tissue Kallikrein decreased GSK-3β activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells. Conclusion These data provide the first direct evidence that Tissue Kallikrein protects against acute-phase MI by promoting neovascularization, restoring regional blood flow and improving cardiac function through the kinin B2 receptor-Akt-GSK-3β and VEGF signalling pathways.
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Tissue Kallikrein Elicits Cardioprotection by Direct Kinin B2 Receptor Activation Independent of Kinin Formation
Hypertension, 2008Co-Authors: Julie Chao, Zhirong Yang, Bo Shen, Makoto Hagiwara, Lee ChaoAbstract:Tissue Kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that Tissue Kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of Tissue Kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue Kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, Tissue Kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester abolished Kallikrein's effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive Kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, Kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that Tissue Kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.
Lee Chao - One of the best experts on this subject based on the ideXlab platform.
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Tissue Kallikrein-kinin therapy in hypertension and organ damage.
Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques, 2014Co-Authors: Julie Chao, Grant Bledsoe, Lee ChaoAbstract:Tissue Kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, Tissue Kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and γ-epithelial Na channel. The Tissue Kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue Kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment Tissue Kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.
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Tissue Kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing.
Biological chemistry, 2010Co-Authors: Julie Chao, Grant Bledsoe, Bo Shen, Lin Gao, Chun-fang Xia, Lee ChaoAbstract:Tissue Kallikrein (KLK1) processes low-molecular weight kininogen to produce vasoactive kinins, which exert biological functions via kinin receptor signaling. Using various delivery approaches, we have demonstrated that Tissue Kallikrein through kinin B2 receptor signaling exhibits a wide spectrum of beneficial effects by reducing cardiac and renal injuries, restenosis and ischemic stroke, and by promoting angiogenesis and skin wound healing, independent of blood pressure reduction. Protection by Tissue Kallikrein in oxidative organ damage is attributed to the inhibition of apoptosis, inflammation, hypertrophy and fibrosis. Tissue Kallikrein also enhances neovascularization in ischemic heart and limb. Moreover, Tissue Kallikrein/kinin infusion not only prevents but also reverses kidney injury, inflammation and fibrosis in salt-induced hypertensive rats. Furthermore, there is a wide time window for Kallikrein administration in protection against ischemic brain infarction, as delayed Kallikrein infusion for 24 h after cerebral ischemia in rats is effective in reducing neurological deficits, infarct size, apoptosis and inflammation. Importantly, in the clinical setting, human Tissue Kallikrein has been proven to be effective in the treatment of patients with acute brain infarction when injected within 48 h after stroke onset. Finally, Kallikrein promotes skin wound healing and keratinocyte migration by direct activation of protease-activated receptor 1.
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Tissue Kallikrein promotes neovascularization and improves cardiac function by the akt glycogen synthase kinase 3β pathway
Cardiovascular Research, 2008Co-Authors: Lee Chao, Bo Shen, Lin Gao, Yuyu Yao, Hang Yin, Robert S Smith, Yuying Liu, Julie ChaoAbstract:Aims We investigated the role of the Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of Tissue Kallikrein on myocardial injury by promoting angiogenesis and blood flow in rats after myocardial infarction (MI). Methods and results Human Tissue Kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3β (Ad.GSK-3βS9A), was injected into rat myocardium after MI. The expression of recombinant human Kallikrein in rat heart significantly improved cardiac function and reduced infarct size 10 days after gene delivery. Kallikrein administration significantly increased myocardial blood flow as well as capillary and arteriole densities in the infarcted myocardium. Kallikrein increased cardiac Akt and GSK-3β phosphorylation in conjunction with decreased GSK-3β activity and the upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). All of Kallikrein’s effects on the myocardium were abrogated by Ad.DN-Akt and Ad.GSK-3βS9A. Moreover, in cultured human aortic endothelial cells, Tissue Kallikrein stimulated capillary tube formation and promoted cell migration; however, these effects were blocked by Ad.DN-Akt, Ad.GSK-3βS9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, Tissue Kallikrein decreased GSK-3β activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells. Conclusion These data provide the first direct evidence that Tissue Kallikrein protects against acute-phase MI by promoting neovascularization, restoring regional blood flow and improving cardiac function through the kinin B2 receptor-Akt-GSK-3β and VEGF signalling pathways.
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Tissue Kallikrein Elicits Cardioprotection by Direct Kinin B2 Receptor Activation Independent of Kinin Formation
Hypertension, 2008Co-Authors: Julie Chao, Zhirong Yang, Bo Shen, Makoto Hagiwara, Lee ChaoAbstract:Tissue Kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that Tissue Kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of Tissue Kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue Kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, Tissue Kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester abolished Kallikrein's effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive Kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, Kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that Tissue Kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.
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Tissue Kallikrein Elicits Cardioprotection by Direct Kinin B2 Receptor Activation Independent of Kinin Formation
Hypertension, 2008Co-Authors: Julie Chao, Zhirong Yang, Bo Shen, Makoto Hagiwara, Lee ChaoAbstract:Tissue Kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that Tissue Kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of Tissue Kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue Kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N ω -nitro-l-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, Tissue Kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N ω -nitro-l-arginine methylester abolished Kallikrein’s effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive Kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, Kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that Tissue Kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.
Kanti D. Bhoola - One of the best experts on this subject based on the ideXlab platform.
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Tissue Kallikrein and kinins in renal disease
Immunopharmacology, 1999Co-Authors: Sarala Naicker, Strini Naidoo, Reena Ramsaroop, D Moodley, Kanti D. BhoolaAbstract:The renal Kallikrein-kinin system is involved in sodium and water homeostasis, blood pressure regulation and inflammation. Tissue Kallikrein and kinin levels were measured in the urine of patients with renal disease and in the urine of living related kidney donors prior to uninephrectomy who served as controls. Tissue Kallikrein and kinin B1 and B2 receptors were immunolocalised by confocal microscopy in renal biopsy material from patients with renal disease and controls (fresh autopsy material and normal kidney Tissue from nephrectomies for malignancy). Urinary Tissue Kallikrein excretion was significantly decreased in patients with mild renal disease (16.6 ± 6.7 ng Tissue Kallikrein (TK)/ng protein; p < 0.05) and more markedly so (1.8 ± 0.7 ng TK/μg protein; p < 0.01) in patients with severe renal failure requiring dialysis compared to normal controls (78.9 ± 31.7 ng TK/μg protein). Basal kinin values were unchanged in patients with renal disease (14 ± 0.8 ng/ml) compared to controls (13.3 ± 0.56 ng/ml). In control kidney Tissue Kallikrein was immunolocalised in the distal connecting tubules and collecting ducts whereas decreased immunolabelling was observed with renal disease. Kinin B2 receptor labelling was present in the entire nephron in the normal control kidney but was reduced with renal disease. While kinin B1 receptor immunolabelling was not observed in the control kidneys, labelling of distal tubules and collecting ducts was noted in renal disease, suggesting an upregulation of B1 receptors in renal parenchymal disease.
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Immunocytochemical analysis of Tissue Kallikrein and the kinin moiety in rheumatoid synovial fluid neutrophils.
British journal of rheumatology, 1997Co-Authors: R J Williams, L M Henderson, Y Naidoo, Bilkish Cassim, C J Elson, Kanti D. BhoolaAbstract:Polymorphonuclear leucocytes (PMNs) from the synovial fluid of patients with rheumatoid arthritis (RA) showed reduced Tissue Kallikrein and kinin immunoreactivity in comparison with blood PMNs from healthy individuals as judged visually using confocal microscopy. Similarly, synovial fluid PMNs exhibited reduced Tissue Kallikrein immunoreactivity as compared with blood PMNs from the same RA patients. Blood PMNs stimulated to degranulate in vitro also displayed less immunostaining for Tissue Kallikrein and kinin than non-stimulated PMNs. By contrast, no difference in kininogen immunostaining was detected between RA synovial fluid PMNs and blood PMNs from healthy people. It is considered that the results support the hypothesis that Tissue Kallikrein, released from the granules of RA synovial fluid PMNs, cleaves the kinin moiety from multifunctional kininogen protein on the surface of the PMNs.
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Tissue Kallikrein in transplant kidney.
Immunopharmacology, 1997Co-Authors: Reena Ramsaroop, Sarala Naicker, T. Naicker, Strini Naidoo, Kanti D. BhoolaAbstract:Literature survey, thus far, has shown a decrease in the excretion of urinary Tissue Kallikrein (TK) in transplant patients with a further reduction of the enzyme during episodes of acute rejection. The study aims were to compare, at cellular and subcellular levels, the localisation of Tissue Kallikrein in biopsies of the transplant kidney to autopsy derived normal renal Tissue. Renal biopsies from eighteen transplant patients with deteriorating renal function were obtained. Immunolabelling for Tissue Kallikrein, using a polyclonal goat anti-TK, antibody raised against recombinant TK, was performed following routine enzymatic, immunofluorescence and electron microscopic techniques. In normal kidney Tissue, TK was immunolocalised in the distal connecting tubules and collecting ducts. By comparison the renal transplant Tissue showed a reduction in the intensity of label, but maintained the sites of localisation. In the sections examined by electron microscopy, although TK was confined mainly at the luminal side of the cell, some label was noted along the basolateral membranes. In the transplant kidneys, there was a reduction in the overall number of gold particles counted, which correlated with the decreased intensity observed on immunocytochemistry. In addition, there was a shift to a basolateral orientation of the immunolabel. Acute rejection is characterised by oedema, tubulitis and vasculitis. Destruction of the tubule cells and leakage of TK into the interstitial Tissue space and the resultant effect of the formed kinins on renal capillary vasculature could explain the observed renal parenchymal oedema and transplant rejection.
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Determination of Tissue Kallikrein and alpha 1-antitrypsin-Tissue Kallikrein complexes in synovial fluid of patients with rheumatoid, osteo and psoriatic arthritis.
Agents and actions. Supplements, 1992Co-Authors: M M Rahman, K. Worthy, Christopher J. Elson, Paul Dieppe, Kanti D. BhoolaAbstract:An enzyme-linked immunosorbant assay was developed to determine Tissue Kallikrein and alpha 1-antitrypsin-Tissue Kallikrein complexes in pooled synovial fluid of patients with rheumatoid, osteo and psoriatic arthritis. Even though basal values could be determined, the addition of synovial fluid shifted the standard curves for both Tissue Kallikrein and alpha 1-antitrypsin-Tissue Kallikrein complex to the right, because of the presence of a novel inhibitor.
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Tissue Kallikrein is associated with prolactin-secreting cells within human growth hormone-secreting adenomas.
The Journal of endocrinology, 1992Co-Authors: T. H. Jones, C. D. Figueroa, C. M. Smith, D. R. Cullen, Kanti D. BhoolaAbstract:Tissue Kallikrein is a serine protease which may be involved in the intracellular processing of prolactin in the anterior pituitary gland. The expression of Tissue Kallikrein, in the rat, is promoted by oestrogen and inhibited by dopamine. Human and rat prolactinomas contain markedly increased amounts of Tissue Kallikrein; this is comparatively reduced if patients are pretreated with the dopamine agonist, bromocriptine, before surgery. Some GH-secreting adenomas are mixed and also contain prolactin-secreting cells. We therefore investigated 27 GH-immunostaining human pituitary adenomas for the presence of immunoreactive Tissue Kallikrein. Sixteen of the adenomas had positive immunostaining for prolactin; eight of these patients had associated clinical hyperprolactinaemia before the tumour was removed. Tissue Kallikrein immunoreactivity was found in ten adenomas, all of which also had prolactin immunopositivity. There was a close relationship between the percentage of cells staining for prolactin and Tissue Kallikrein but not for GH. A further eight adenomas had patchy positivity, i.e. less than 1% of cells immunostained for Tissue Kallikrein and six of these also had some prolactin-staining cells. Nine out of eleven purely GH-staining adenomas had no Tissue Kallikrein immunopositivity, the remaining two showing patchy staining. A review of bromocriptine responsiveness, as assessed by mean GH hormone levels during oral glucose tolerance tests before and after therapy was commenced, indicated that patients with adenomas which stained for prolactin and Tissue Kallikrein were more likely to respond to bromocriptine than those which failed to do so.
Eleftherios P Diamandis - One of the best experts on this subject based on the ideXlab platform.
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Human Tissue Kallikrein 9: production of recombinant proteins and specific antibodies.
Biological chemistry, 2006Co-Authors: Nader Memari, Linda Grass, Terukazu Nakamura, Inci Karakucuk, Eleftherios P DiamandisAbstract:Human Tissue Kallikreins (genes, KLKs; proteins, hKs) are a subgroup of hormonally regulated serine proteases. Two Tissue Kallikreins, namely hK2 and hK3 (prostate-specific antigen, PSA), are currently used as serological biomarkers of prostate cancer. Human Tissue Kallikrein 9 (KLK9) is a newly identified member of the Tissue Kallikrein gene family. Recent reports have indicated that KLK9 mRNA is differentially expressed in ovarian and breast cancer and has prognostic value. Here, we report the production of recombinant hK9 (classic form) using prokaryotic and mammalian cells and the generation of polyclonal antibodies. Total testis Tissue mRNA was reverse-transcribed to cDNA, amplified, cloned into a pET/200 TOPO plasmid vector, and transformed into E. coli cells. hK9 was purified and used as an immunogen to generate polyclonal antibodies. Full-length KLK9 cDNA was also cloned in the vector pcDNA3.1 and was expressed in CHO cells. The identity of hK9 was confirmed by mass spectrometry. hK9 rabbit antiserum displayed no cross-reactivity with other Tissue Kallikreins and could specifically recognize E. coli- and CHO-derived hK9 on Western blots. hK9 was mainly detected in testis and seminal vesicles by Western blotting. The reagents generated here will help to define the physiological role of this Tissue Kallikrein and its involvement in human disease.
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the new human Tissue Kallikrein gene family structure function and association to disease
Endocrine Reviews, 2001Co-Authors: George M Yousef, Eleftherios P DiamandisAbstract:The human Tissue Kallikrein gene family was, until recently, thought to consist of only three genes. Two of these human Kallikreins, prostate-specific antigen and human glandular Kallikrein 2, are currently used as valuable biomarkers of prostatic carcinoma. More recently, new Kallikrein-like genes have been discovered. It is now clear that the human Tissue Kallikrein gene family contains at least 15 genes. All genes share important similarities, including mapping at the same chromosomal locus (19q13.4), significant homology at both the nucleotide and protein level, and similar genomic organization. All genes encode for putative serine proteases and most of them are regulated by steroid hormones. Recent data suggest that at least a few of these Kallikrein genes are connected to malignancy. In this review, we summarize the recently accumulated knowledge on the human Tissue Kallikrein gene family, including gene and protein structure, predicted enzymatic activities, Tissue expression, hormonal regulation, and alternative splicing. We further describe the reported associations of the human Kallikreins with various human diseases and identify future avenues for research.
Grant Bledsoe - One of the best experts on this subject based on the ideXlab platform.
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Tissue Kallikrein-kinin therapy in hypertension and organ damage.
Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques, 2014Co-Authors: Julie Chao, Grant Bledsoe, Lee ChaoAbstract:Tissue Kallikrein is a serine proteinase that cleaves low molecular weight kininogen to produce kinin peptides, which in turn activate kinin receptors to trigger multiple biological functions. In addition to its kinin-releasing activity, Tissue Kallikrein directly interacts with the kinin B2 receptor, protease-activated receptor-1, and γ-epithelial Na channel. The Tissue Kallikrein-kinin system (KKS) elicits a wide spectrum of biological activities, including reducing hypertension, cardiac and renal damage, restenosis, ischemic stroke, and skin wound injury. Both loss-of-function and gain-of-function studies have shown that the KKS plays an important endogenous role in the protection against health pathologies. Tissue Kallikrein/kinin treatment attenuates cardiovascular, renal, and brain injury by inhibiting oxidative stress, apoptosis, inflammation, hypertrophy, and fibrosis and promoting angiogenesis and neurogenesis. Approaches that augment Tissue Kallikrein-kinin activity might provide an effective strategy for the treatment of hypertension and associated organ damage.
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Tissue Kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing.
Biological chemistry, 2010Co-Authors: Julie Chao, Grant Bledsoe, Bo Shen, Lin Gao, Chun-fang Xia, Lee ChaoAbstract:Tissue Kallikrein (KLK1) processes low-molecular weight kininogen to produce vasoactive kinins, which exert biological functions via kinin receptor signaling. Using various delivery approaches, we have demonstrated that Tissue Kallikrein through kinin B2 receptor signaling exhibits a wide spectrum of beneficial effects by reducing cardiac and renal injuries, restenosis and ischemic stroke, and by promoting angiogenesis and skin wound healing, independent of blood pressure reduction. Protection by Tissue Kallikrein in oxidative organ damage is attributed to the inhibition of apoptosis, inflammation, hypertrophy and fibrosis. Tissue Kallikrein also enhances neovascularization in ischemic heart and limb. Moreover, Tissue Kallikrein/kinin infusion not only prevents but also reverses kidney injury, inflammation and fibrosis in salt-induced hypertensive rats. Furthermore, there is a wide time window for Kallikrein administration in protection against ischemic brain infarction, as delayed Kallikrein infusion for 24 h after cerebral ischemia in rats is effective in reducing neurological deficits, infarct size, apoptosis and inflammation. Importantly, in the clinical setting, human Tissue Kallikrein has been proven to be effective in the treatment of patients with acute brain infarction when injected within 48 h after stroke onset. Finally, Kallikrein promotes skin wound healing and keratinocyte migration by direct activation of protease-activated receptor 1.
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the Tissue Kallikrein kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction
Biological Chemistry, 2006Co-Authors: Julie Chao, Grant Bledsoe, Hang Yin, Lee ChaoAbstract:Tissue Kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue Kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human Tissue Kallikrein or kinin B2 receptor are permanently hypotensive, and somatic Kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, Kallikrein gene delivery or Kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, Tissue Kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that Tissue Kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that Kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.
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Tissue Kallikrein attenuates salt induced renal fibrosis by inhibition of oxidative stress
Kidney International, 2004Co-Authors: Jenny J Zhang, Grant Bledsoe, Lee Chao, Kazuo Kato, Julie ChaoAbstract:Tissue Kallikrein attenuates salt-induced renal fibrosis by inhibition of oxidative stress. Background High salt intake induces hypertension, cardiac hypertrophy, and progressive renal damage. Progressive renal injury is the consequence of a process of destructive fibrosis. Using gene transfer approach, we have shown that the Tissue Kallikrein-kinin system (KKS) plays an important role in protection against renal injury in several hypertensive ratmodels. In this study, we further investigated the effect and potential mechanisms mediated by Kallikrein on salt-induced renal fibrosis. Methods Adenovirus harboring the human Tissue Kallikrein gene was delivered intravenously into Dahl salt-sensitive (DSS) rats on a high salt diet for 4 weeks. Two weeks after gene delivery, the effect of Kallikrein on renal fibrosis was examined by biochemical and histologic analysis. Results Kallikrein gene delivery resulted in reduced blood urea nitrogen (BUN), urinary protein and albumin levels in DSS rats on a high salt diet. Expression of recombinant human Tissue Kallikrein was detected in the sera and urine of rats injected with the Kallikrein gene. Histologic investigation showed that Kallikrein gene delivery significantly reduced glomerular and tubular fibrosis scores and collagen deposition, as well as renal cell proliferation, compared to rats on a high salt diet injected with control virus. Kallikrein gene transfer significantly increased nitric oxide and cyclic guanosine monophosphate (cGMP) levels in conjunction with reduced salt-induced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase activity, superoxide production, transforming growth factor-β1 (TGF-β1) mRNA and protein levels, and TGF-β1 immunostaining. Conclusion These results indicate that Tissue Kallikrein protects against renal fibrosis in hypertensive DSS rats through increased nitric oxide bioavailability and suppression of oxidative stress and TGF-β expression.
