The mRNAs of Prekallikrein, Factors XI and XII, and Kininogen, Components of the Contact Phase Cascade Are Differentially Expressed in Multiple Non-hepatic Human Tissues

Neth, Peter; Arnhold, Marianne; Nitschko, Hans; Fink, Edwin

doi:10.1055/s-0037-1615961

Cited by 32 publications

(29 citation statements)

References 15 publications

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“…Although hepatocytes were considered to synthesise plasma prekallikrein and PPK mRNA expression was highest in the liver (Neth et al, 2001), direct evidence of its presence in the liver was obtained only when the enzyme was demonstrated in isolated hepatocytes by immunofluorescence (Henderson et al, 1992). In the current study, we confirmed the localisation of PPK/PK in human hepatocytes ( Figure 3A).…”

Section: Liversupporting

confidence: 77%

“…With 0.3% compared to liver, mRNA expression in lung was very low (Neth et al, 2001). Nevertheless, as in the epithelium of other glandular organs, epithelial cells forming the respiratory epithelium stained positively for PPK/PK.…”

Section: Respiratory Tractmentioning

confidence: 91%

“…Kidney exhibited the third highest PPK mRNA expression (24.5% compared to liver; Neth et al, 2001) and therefore significant positive immunostaining for PK/ PPK was expected. In the current study we observed intense staining of PPK/PK in cells of the proximal tubules ( Figure 2C,D), distal tubules and collecting ducts ( Figure 2E).…”

Section: Kidneymentioning

confidence: 95%

“…Recent studies by quantitative RT-PCR demonstrated that the PPK gene is transcribed not only in the liver, but also at significant levels in non-hepatic human tissues ( Figure 1, from Neth et al, 2001). Here we examined the question as to whether PPK mRNA in extrahepatic tissues is actually translated into the zymogen protein.…”

Section: Introductionmentioning

confidence: 99%

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Cellular expression of plasma prekallikrein in human tissues

Fink

Bhoola

Snyman

et al. 2007

BCHM

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Plasma prekallikrein (PPK) is synthesised in hepatocytes and secreted into the blood, where it participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. Recently we demonstrated by quantitative RT-PCR that the human PPK gene is transcribed not only in the liver, but also in various non-hepatic human tissues at significant levels. However, up to now no reliable information is available concerning protein synthesis in the corresponding human tissues. Here we demonstrate by immunohistochemical studies that PPK or plasma kallikrein (PK) is localised in cells of different embryologically derived human tissues. In the human nephron, single cells of the distal tubules stained intensely, while the cytoplasm of cells forming proximal tubules and collecting ducts stained uniformly. PPK/PK was localised in hepatic epithelial cells of the liver, in cells of the pancreatic islet of Langerhans, in the interstitial Leydig cells of the testes, in the follicular and thecal granulosa cells of the ovary, and in the parotid gland, oesophagus, skin, respiratory tract, prostate and breast. We conclude that the cellular localisation of PPK/PK in multiple different progenitorderived cells indicates specific cellular functions of this enzyme, in addition to its known function in the blood.

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Section: Liversupporting

confidence: 77%

Section: Respiratory Tractmentioning

confidence: 91%

Section: Kidneymentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Cellular expression of plasma prekallikrein in human tissues

Fink

Bhoola

Snyman

et al. 2007

BCHM

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“…These include secreted enzymes, such as trypsin I, II (Paju et al, 2000;Bjartell et al, 2005) and IV (Takeuchi et al, 1999;Cottrell et al, 2004); other more complex secreted serine proteinases, containing modular nonproteolytic domains, such as factor XIIa (Takeuchi et al, 1999), plasma kallikrein (Neth et al, 2001;Fink et al, 2007), urokinase (also known as urinary plasminogen activator, uPA; Gavrilov et al, 2001;Riddick et al, 2005;Usher et al, 2005) and protein C (He et al, 1995;Takeuchi et al, 1999); the multi-serine proteinase domain containing enzymes polyserase-2 and -3 (Cal et al, 2005(Cal et al, , 2006; the glycosyl-phosphatidylinositol membraneanchored serine proteinase prostasin (Chen et al, 2001); as well as nine members of the type II transmembrane serine proteinase (TTSP) sub-family (Hooper et al, 2001;Netzel-Arnett et al, 2003) including hepsin, enteropeptidase (Cottrell et al, 2004), matriptase/MT-SP1 (Saleem et al, 2006), TMPRSS2 (Lin et al, 1999), TMPRSS3 (Scott et al, 2001), TMPRSS13 (Kim et al, 2001), human airway trypsin-like proteinase (HAT) (Hahner et al, 2005), DESC1 (Lang and Schuller, 2001) and the multi-catalytic domain TTSP polyserase-1 (Okumura et al, 2006). It is also interesting to note the co-expression in prostatederived cell lines of trypsinogen I, II and IV and the in vivo Brought to you by | University of Queensland -UQ Library Authenticated Download Date | 9/14/15 3:38 AM activator of these enzymes, the TTSP enteropeptidase (Light and Janska, 1989;Kitamoto et al, 1994).…”

Section: Par Cleavage By Other Prostatic Trypsin-like Serine Proteinasesmentioning

confidence: 99%

Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs)

Ramsay

Reid

Adams

et al. 2008

BCHM

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The prostate is a site of high expression of serine proteinases including members of the kallikrein-related peptidase (KLK) family, as well as other secreted and membrane-anchored serine proteinases. It has been known for some time that members of this enzyme family elicit cellular responses by acting directly on cells. More recently, it has been recognised that for serine proteinases with specificity for cleavage after arginine and lysine residues (trypsin-like or tryptic enzymes) these cellular responses are often mediated by cleavage of members of the proteinase-activated receptor (PAR) family -a four member sub-family of G protein-coupled receptors. Here, we review the expression of PARs in prostate, the ability of prostatic trypsin-like KLKs and other prostateexpressed tryptic enzymes to cleave PARs, as well as the prostate cancer-associated consequences of PAR activation. In addition, we explore the dysregulation of trypsin-like serine proteinase activity through the loss of normal inhibitory mechanisms and potential interactions between these dysregulated enzymes leading to aberrant PAR activation, intracellular signalling and cancer-promoting cellular changes.

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Accumulation of high molecular weight kininogen in the brains of Alzheimer's disease patients may affect microglial function by altering phagocytosis and lysosomal cathepsin activity

Zamolodchikov

Duffield

Macdonald

et al. 2022

Alzheimer's & Dementia

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Increased activation of the contact system protein high molecular weight kininogen (HK) has been shown in plasma and cerebrospinal fluid of Alzheimer's disease (AD) patients, but its potential role in the brain has not been explored. We assessed HK levels in brain tissue from 20 AD patients and controls and modeled the effects of HK on microglia-like cells in culture. We show increased levels of HK in the hippocampus of AD patients, which colocalized with amyloid beta (Aβ) deposits and activated microglia.Treatment of microglia with HK led to cell clustering and elevated levels of phagocytosed Aβ. We demonstrate that microglia internalize HK and traffic it to lysosomes, which is accompanied by reduced activity of lysosomal cathepsins L and S. Our results suggest that HK accumulation in the AD hippocampus may alter microglial uptake and degradation of Aβ fibrils, possibly contributing to microglial dysfunction in AD. K E Y W O R D SAlzheimer's disease, cathepsin, high molecular weight kininogen, microglia, phagocytosis NARRATIVE Contextual backgroundMicroglial activation has long been associated with amyloid beta (Aβ) and tau pathology in Alzheimer's disease (AD), but whether this association is a contributing factor to disease development or a consequence of other pathological processes is unclear. The recent identification of AD risk variants in genes that are preferentially or exclusively expressed in microglia (e.g., SPI1, BIN1, TREM2, CD33) suggests that microglia may indeed play a key role in AD pathogenesis. Microglia are well poised to affect neuronal function through their roles in synaptic pruning, trophic support, and inflammatory response, all of which when perturbed can lead to neuronal dysfunction. However, the mechanisms behind compromised microglial function in AD patients remain unclear, and a better understanding of the processes that contribute to the modulation of microglia function in AD is needed. Recent work has implicated the contact activation system in AD pathogenesis. The contact system, which triggers proinflammatory and procoagulant processes in the circulation, is initiated when circulating coagulation factor XII (FXII) is activated by negatively charged surfaces, triggering the intrinsic coagulation and kallikrein-kinin pathways. Activation of the kallikrein-kinin pathway results in the cleavage of high molecular weight kininogen (HK) to generate two molecules: bradykinin and cleaved HK (HKc). Bradykinin is a proinflammatory peptide that regulates diverse processes including prostaglandin release, vasodilation, vascular permeability, and pain. In addition to being the parent molecule of bradykinin, HKc has been shown to have a wide variety of functions including cysteine protease inhibition, angiogenesis, and a modulation of adhesion, migration, apoptosis, and cytokine release in various cell types. 1-4Increased activation of the contact system, as measured by increased HKc and bradykinin levels, has been observed in the plasma of AD patients and mouse models, [5][6][7] suggesting...

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The mRNAs of Prekallikrein, Factors XI and XII, and Kininogen, Components of the Contact Phase Cascade Are Differentially Expressed in Multiple Non-hepatic Human Tissues

Cited by 32 publications

References 15 publications

Cellular expression of plasma prekallikrein in human tissues

Cellular expression of plasma prekallikrein in human tissues

Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs)

Accumulation of high molecular weight kininogen in the brains of Alzheimer's disease patients may affect microglial function by altering phagocytosis and lysosomal cathepsin activity

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