Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracapillary glomerulonephritis are associated with fibrin deposition in the urinary space of the glomerulus. Such deposits were correlated with the severity of the disease and with a poor renal outcome. Fibrin formation involves an activation of the coagulation cascade either through the intrinsic pathway, Hageman factor being activated by the altered glomerular basement membrane, either by the extrinsic pathway, infiltrating monocytes and glomerular cells exhibiting a procoagulant activity i.e. thromboplastin or tissue factor. Treatments with heparin or warfarin were shown to decrease the severity of experimental glomerular diseases. A similar beneficial effect was obtained with a monocyte-depleting serum and more recently with a treatment by a tissue type plasminogen activator. Glomerular cells also produce a fibrinolytic activity which could be too low or uneffective on extracapillary fibrin deposits if they contain high amounts of plasminogen activator inhibitors. Thrombin has procoagulant activity, antifibrinolytic activity and has cellular chemotactic and proliferative effects. It could play a major role in the pathogenesis of crescent formation.
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PMID:[Role of hemostasis in the formation of crescents in extracapillary glomerulonephritis]. 129 84

We carried out an immunohistochemical study of tissue-type plasminogen activator (PA) and urokinase-type PA, and their inhibitors, PA inhibitor-1 and PA inhibitor-2, using renal biopsy specimens obtained from 86 patients with various forms of glomerulonephritis. The controls were four normal renal tissue specimens. On immunofluorescent observation, granular staining for tissue-type PA was found to be distributed along the glomerular capillary walls. The fluorescence was weak in the normal renal tissue and occasionally intense in the tissues of patients with IgA nephritis, minimal change nephrotic syndrome, and lupus nephritis. PA inhibitor-1 was abundant in the glomerular epithelial cells and scarce in the mesangial area and glomerular capillary lumens of the normal renal tissues. This was confirmed by immunoelectron microscopy using gold staining. The fluorescence of PA inhibitor-1 was weaker in some specimens of nephritic tissues than in the normal renal tissues. Urokinase-type PA and PA inhibitor-2 were negative within the glomeruli in all the specimens. In the glomerulonephritic tissues which were fibrin deposition-positive, tissue-type PA expression in the glomeruli tended to be strong. An association between fibrin deposition and PA inhibitor-1 staining was not clear. These data suggest that expression of tissue-type PA in the glomeruli increases in association with fibrin deposition.
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PMID:Tissue-type plasminogen activator and its inhibitor in human glomerulonephritis. 138 27

TGF-beta plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-beta expression leads to increased synthesis and deposition of extracellular matrix components while administration of anti-serum to TGF-beta suppresses the major manifestations of the disease. We hypothesized that TGF-beta might also enhance matrix accumulation by decreasing matrix turnover via effects on protease/protease inhibitor balance. Plasmin is a potent protease capable of degrading a variety of matrix molecules. Plasmin generation from plasminogen is regulated by plasminogen activator(s) (PA) and plasminogen activator inhibitor(s) (PAI). In this study PA activity was markedly reduced and PAI-1 synthesis dramatically increased when TGF-beta was added to normal glomeruli. Diseased glomeruli also showed decreased PA activity, increased PAI-1 synthesis and increased PAI-1 deposition into matrix. Administration of anti-TGF-beta serum to glomerulonephritic rats blocked the expected increase in glomerular PAI-1 deposition. Thus changes in the PA/PAI balance favoring accumulation of matrix are induced by TGF-beta in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-beta production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-beta enhances the matrix accumulation characteristic of many glomerular diseases.
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PMID:Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. 147 81

It is a well known fact that intraglomerular coagulation plays an important role in the development of human primary glomerular diseases. However, the precise mechanism of intraglomerular coagulation, and intraglomerular coagulability and/or fibrinolytic activity remains obscure. The present study was aimed to elucidate the role of the intraglomerular coagulation and fibrinolysis in human primary glomerular diseases. Subjects enrolled in this study were 27 patients with minimal change nephrotic syndrome (MCNS), 14 patients with focal glomerular sclerosis (FGS), 36 patients with membranous nephropathy (MN), 161 patients with mesangial proliferative glomerulonephritis (mesPGN), 9 patients with membranoproliferative glomerulonephritis (MPGN), and 40 healthy volunteers as controls. Normal human renal cortex as controls of isolated intraglomerular plasminogen activator activity (PAA) was obtained at the time of nephrectomy from the normal pole of kidneys removed because of an opposite pole tumor. Urinary urokinase (UK), fibrinopeptide A (FPA) and fibrinopeptide B beta 15-42 (B beta 15-42) antigens were measured by RIA. Urinary tissue plasminogen activator (t-PA) antigen was measured by ELISA. Urinary fibrin/fibrinogen degradation products (FDP) were measured by latex agglutination method. Moreover, PAA was measured by 125I-fibrin films. The following results were obtained: 1) In primary glomerular diseases, levels of urinary UK and t-PA were significantly lower than those in healthy volunteers, 2) Urinary UK and t-PA showed gradual decrease along with the development of mesangial proliferation, 3) Urinary UK and t-PA were significantly correlated with both the urinary FPA and B beta 15-42, 4) In mesPGN and FGS, PAA was significantly lower than that in normal controls, 5) PAA was significantly correlated with urinary UK, t-PA, FPA and B beta 15-42, 6) Urinary UK and t-PA in the patients with urinary FDP were significantly lower than those in patients without urinary FDP, 7) Urinary UK, t-PA and PAA were significantly lower in patients with intraglomerular fibrin deposition than those in patients without fibrin depositions. These findings suggest that the decrease of urinary UK and t-PA levels and the diminution of isolated intraglomerular plasminogen activator activity contribute to the progression of primary glomerular diseases.
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PMID:[Intraglomerular coagulation and fibrinolysis in human primary glomerular diseases]. 177 Jun 32

Human glomerular epithelial cells (GECs) in culture synthesize single-chain, urokinase-type plasminogen activator (SC-uPA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1) and possess specific membrane-binding sites for u-PA. Using purified 125I-alpha thrombin, we demonstrate here the presence of two populations of specific binding sites for thrombin on GECs (1.Kd = 4.3 +/- 1.0 x 10(-10) M, 5.4 +/- 1.4 x 10(4) M sites per cell, 2. Kd = 1.6 +/- 0.5 x 10(-8) M, 7.9 +/- 1.8 x 10(5) sites per cell). Purified human alpha thrombin promoted the proliferation of GECs and induced a time- and dose-dependent increase of SC-uPA, t-PA, and PAI-1 antigens released by GECs. Thrombin-mediated increase in antigen was paralleled by an increase in the levels of corresponding u-PA and PAI-1 messenger RNA. In contrast, thrombin decreased u-PA activity in conditioned medium. This discrepancy between u-PA antigen and u-PA activity was explained by a limited proteolysis of SC-uPA by thrombin, leading to a two-chain form detected by immunoblotting and that could not be activated by plasmin. Thrombin also decreased the number of u-PA binding sites on GECs (p less than 0.05) without changing receptor affinity. Hirudin inhibited the binding and the cellular effects of thrombin, whereas thrombin inactivated by diisopropylfluorophosphate had no effect, indicating that both membrane binding and catalytic activity of thrombin were required. We conclude that thrombin, through specific membrane receptors, stimulates proliferation of GECs and decreases the fibrinolytic activity of GECs both at the cell surface and in the conditioned medium. These results suggest that thrombin could be involved in the pathogenesis of extracapillary proliferation and persistency of fibrin deposits in crescentic glomerulonephritis.
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PMID:Thrombin increases proliferation and decreases fibrinolytic activity of kidney glomerular epithelial cells. 184 34

Fibrin deposition in kidney is a common event in some forms of human and experimental glomerulonephritis, and is thought to result from local activation of blood coagulation and/or impaired removal by the fibrinolytic system. We studied the urinary procoagulant and fibrinolytic activities in 46 patients with renal disease (26 with IgA nephritis, 13 with other forms of glomerulonephritis and 7 with non-inflammatory kidney disease) and in 15 matched healthy subjects, as possible indicators of the coagulation-fibrinolysis balance in kidney. Procoagulant activity was slightly but not significantly increased in patients with serum creatinine levels higher than 1.5 mg/dl (group II) as compared with patients with normal creatinine (group I) and controls. It was identified as tissue factor by biological criteria (dependence on factor VII). Fibrinolysis studies showed that both plasminogen activator activity and urokinase antigen were significantly lower in group II than in group I patients and controls (P less than 0.0005). Reduced fibrinolytic activity in patients' urine was due to decreased excretion of urokinase since no inhibitor was detected by both fibrin autography and functional assay. No differences were found between patients and controls in plasma fibrinolytic activity, plasminogen activator inhibitor, and procoagulant activity of blood monocytes. The urinary changes in severe renal disease may reflect an unbalance of the coagulation-fibrinolysis equilibrium in kidney and might be of pathogenetic and clinical relevance.
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PMID:Urinary procoagulant and fibrinolytic activity in human glomerulonephritis. Relationship with renal function. 191 Jan 25

The current theories on the pathogenesis of post streptococcal glomerulonephritis are reviewed. Clinical findings during the last decades have indicated the involvement of an immune mechanism. However, the lack of adequate animal models has hampered a thorough understanding of the development of the disease from the initiating infection to the final glomerulonephritic sequelae. Several facts point to the presence of a special nephritogenic streptococcal factor which is directly or indirectly involved in the pathogenesis. There seems to be a plasminogen activator (PA) with unique properties. Data on animals experiments using streptococci producing this factor as well as on injections of the pure substance are presented and correlated to the finding in post streptococcal glomerulonephritis in man.
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PMID:Hypothesis on the pathogenesis of post-streptococcal glomerulonephritis based on recent clinical and experimental research. 209 Jan 47

The persistency of fibrin deposits in the kidney during renal diseases could reflect either a defective release of plasminogen activators (PA) or a local excess of PAI. In order to investigate this question, we studied human renal biopsies by immunofluorescence technique with specific antibodies for fibrin, tissue-type plasminogen activator (t-PA), urokinase (u-PA), PAI-1 and PAI-2. By this technique t-PA could be detected in the glomerular flocculus and the endothelium of small arteries of the normal control kidneys. We failed to detect significant fluorescence with other antibodies in normal kidneys. Conversely, in cases of vascular nephropathy with thrombosis the positive fluorescence obtained with anti-fibrin antibodies at the site of thrombosis was associated with a positive fluorescence with anti-PAI-1 and to a lesser extent with anti-t-PA antibodies. u-PA and PAI-2 were not detected in these lesions. Similarly in the most severe forms of crescentic glomerulonephritis, extracapillary fibrin deposits were associated with PAI-1. In one case u-PA was also detected. This is in agreement with our previous findings that glomerular epithelial cells release both PAI-1 and the inactive form of u-PA (pro u-PA). Thus, our results support the hypothesis that PAI-1, which is able to inhibit both t-PA and u-PA, may play a major role in the persistency of fibrin deposits in the human kidneys during pathological conditions.
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PMID:Plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies. 210 50

Besides its procoagulant activity, thrombin has been shown to stimulate cell proliferation and to regulate the fibrinolytic pathway. We report here the effect of purified human alpha thrombin on the synthesis of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) by cultured human mesangial cells. Thrombin (0 to 2.5 U/ml) increased in a time- and dose-dependent manner the production of t-PA and PAI-1 (2- to 3-fold increase of secreted t-PA and PAI-1 release during a 24 hour incubation). This effect was associated with a twofold increase in DNA synthesis measured by 3H-thymidine incorporation. Zymographic analysis and reverse fibrin autography showed that thrombin also increased the level of the 110 Kd t-PA-PAI-1 complex, whereas PAI-1 was present as a free 50 Kd form in the culture medium conditioned by unstimulated and thrombin-stimulated cells. Free t-PA was never observed. Both membrane binding and catalytic activity of thrombin were required since the effects of 1 U/ml thrombin were inhibited by addition 2 U/ml hirudin, which inhibits the membrane binding and catalytic activity of thrombin, and since DFP-inactivated thrombin, which has the ability to bind but which has no enzymatic activity, did not induce t-PA or PAI-1. Gamma thrombin, which does not bind to thrombin receptor, did not increase t-PA and PAI-1 releases. The effects of thrombin were probably mediated by protein kinase C activation since H7, an inhibitor of protein kinases, inhibited significantly thrombin effects on t-PA and PAI-1 production, and since addition of an activator of protein kinase A, 8-bromocyclic AMP (100 microM), induced a significant inhibition of the thrombin effect. The effects of thrombin were also suppressed by 1.25 micrograms/ml alpha amanitin, suggesting a requirement of de novo RNA synthesis. Northern blot analysis indicated that thrombin induced an increase in the mRNA levels of t-PA and of PAI-1. We conclude that thrombin increases DNA synthesis in human mesangial cells and enhances the synthesis of both t-PA and PAI-1. The latter is released in a large excess as compared to t-PA. Hence, thrombin may have a role in provoking a localized hypofibrinolytic state and may contribute to the persistence of glomerular fibrin deposits during proliferative glomerulonephritis.
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PMID:Thrombin regulates components of the fibrinolytic system in human mesangial cells. 212 90

The concentrations of two different plasminogen activators(PAs), urokinase (UK), tissue-type plasminogen activator (t-PA) and urinary trypsin inhibitor (UTI) were determined in the urine and blood from 48 normal subjects and 92 patients with glomerulonephritis using highly sensitive enzyme immunoassay (EIA). The values of UK clearance were approximately 1.5-fold larger than those of creatinine clearance and at least 60.8% of UK was reabsorbed in the renal tubules, which suggest that one of major secretion site of UK is located in the outer region of the glomerular basement membrane (GBM), that is glomerular epithelium. Decreased urinary excretion of UK was observed in the glomerular disease depending on their severity and correlated with the increasing degree of FDP D-dimer excretion. On the other hand, the values of t-PA clearance were quite smaller than those of creatinine clearance, which suggest that urinary t-PA originated from the blood circulation or the inner side of the GBM (possibly glomerular endothelium) and filtrated from the GBM. Like UK, urinary t-PA also decreased in glomerular diseases. UTI which is highly anionic and has a comparable size with albumin was excreted increasingly in glomerulo-nephritis due to loss of the anionic charge barrier of the GBM. No significant correlations were noted between UTI excretion and UK or t-PA excretion.
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PMID:Urinary UK, t-PA and urinary trypsin inhibitor in health and glomerular diseases. 251 8


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