scholarly journals Protective role of thrombin activatable fibrinolysis inhibitor in obstructive nephropathy-associated tubulointerstitial fibrosis

2007 ◽  
Vol 6 (1) ◽  
pp. 139-146 ◽  
Author(s):  
N. E. BRUNO ◽  
Y. YANO ◽  
Y. TAKEI ◽  
E. C. GABAZZA ◽  
L. QIN ◽  
...  
Keyword(s):  
Protective Role ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

scholarly journals Dicer deficiency in proximal tubules exacerbates renal injury and tubulointerstitial fibrosis and upregulates Smad2/3

2018 ◽  
Vol 315 (6) ◽  
pp. F1822-F1832 ◽  
Author(s):  
Zhengwei Ma ◽  
Qingqing Wei ◽  
Ming Zhang ◽  
Jian-Kang Chen ◽  
Zheng Dong
Keyword(s):  
Kidney Disease ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Proximal Tubules ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Pathological Feature ◽  
Tubular Injury

Renal fibrosis is a common pathological feature in chronic kidney disease (CKD), including diabetic kidney disease (DKD) and obstructive nephropathy. Multiple microRNAs have been implicated in the pathogenesis of both DKD and obstructive nephropathy, although the overall role of microRNAs in tubular injury and renal fibrosis in CKD is unclear. Dicer (a key RNase III enzyme for microRNA biogenesis) was specifically ablated from kidney proximal tubules in mice via the Cre-lox system to deplete micoRNAs. Proximal tubular Dicer knockout (PT- Dicer KO) mice and wild-type (WT) littermates were subjected to streptozotocin (STZ) treatment to induce DKD or unilateral ureteral obstruction (UUO) to induce obstructive nephropathy. Renal hypertrophy, renal tubular apoptosis, kidney inflammation, and tubulointerstitial fibrosis were examined. Compared with WT mice, PT- Dicer KO mice showed more severe tubular injury and renal inflammation following STZ treatment. These mice also developed higher levels of tubolointerstitial fibrosis. Meanwhile, PT- Dicer KO mice had a significantly higher Smad2/3 expression in kidneys than WT mice (at 6 mo of age) in both control and STZ-treated mice. Similarly, UUO induced more severe renal injury, inflammation, and interstitial fibrosis in PT- Dicer KO mice than WT. Although we did not detect obvious Smad2/3 expression in sham-operated mice (2–3 mo old), significantly more Smad2/3 was induced in obstructed PT- Dicer KO kidneys. These results supported a protective role of Dicer-dependent microRNA synthesis in renal injury and fibrosis development in CKD, specifically in DKD and obstructive nephropathy. Depletion of Dicer and microRNAs may upregulate Smad2/3-related signaling pathway to enhance the progression of CKD.

The C1542G and G505A Polymorphisms of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) in Patients with Thrombotic Microangiopathies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2141-2141
Author(s):  
Christoph Sucker ◽  
Firuseh Farokhzad ◽  
Fieras Dahhan ◽  
Michael Schmitz ◽  
Gerd R. Hetzel ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Arterial Thrombosis ◽  
Case Control ◽  
Thrombotic Microangiopathies ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Increased Risk ◽  
Fibrinolysis Inhibitor ◽  
Inflammatory Processes ◽  
History Of

Abstract Background Thrombotic microangiopathies are characterized by vascular microthromboses, microangiopathic hemolytic anemia, and thrombocytopenia. Although recent research has elucidated the pathogenesis of these rare thrombotic disorders to some extent, the determinants contributing to the onset and modulating the severity are largely unknown. It is likely that risk factors of venous and arterial thrombosis also play a role in this clinical setting. Patients and Methods In the present study, we used a case-control and a case-only design, enrolling 23 patients (mean age [± SD] 35 ± 11 years) with a history of thrombotic microangiopathy and 689 control subjects to assess the role of gene polymorphisms of the thrombin-activatable fibrinolysis inhibitor (TAFI). Results The prevalence of the TAFI decreasing G/G genotype of the C1542G polymorphism was significantly higher in patients compared to controls (odds ratio 3.88; 95 % CI 1.07 – 11.47; p=0.02). In addition, in a case-only design the TAFI 1542 G allele was more prevalent in patients suffering from a severe course compared to those with a mild or moderate course (odds ratio 20; 95 % CI 1.85 – 216.17; p=0.009). By contrast, no such association was found for the TAFI G505A polymorphism. Conclusions Our study shows an association of the TAFI decreasing 1542 G/G genotype with an increased risk for thrombotic microangiopathies and a more severe course. This finding might be explained by the role of TAFI as an inhibitor of local inflammatory processes.

Role of Zinc Ions in Activation and Inactivation of Thrombin-Activatable Fibrinolysis Inhibitor†

Biochemistry ◽  
2002 ◽  
Vol 41 (4) ◽  
pp. 1211-1216 ◽  
Author(s):  
Pauline F. Marx ◽  
Bonno N. Bouma ◽  
Joost C. M. Meijers
Keyword(s):  
Zinc Ions ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

Fine mapping of quantitative trait nucleotides underlying thrombin-activatable fibrinolysis inhibitor antigen levels by a transethnic study

Blood ◽  
2006 ◽  
Vol 108 (5) ◽  
pp. 1562-1568 ◽  
Author(s):  
Corinne Frère ◽  
David-Alexandre Tregouet ◽  
Pierre-Emmanuel Morange ◽  
Noémie Saut ◽  
Dinar Kouassi ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Phylogenetic Study ◽  
Strong Linkage Disequilibrium ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Gene Coding ◽  
Fibrinolysis Inhibitor ◽  
Out Of Africa ◽  
Independent Effects ◽  
Insight Into

Recent studies revisiting the association between plasma thrombin-activatable fibrinolysis inhibitor (TAFI) Ag levels and polymorphisms of the CPB2 gene (coding for TAFI) suggested that TAFI Ag levels were influenced by 2 major quantitative trait nucleotides (QTNs) in European whites. However, the strong linkage disequilibrium (LD) between CPB2 polymorphisms in European whites did not allow one to distinguish which polymorphisms could be the putative QTNs. To get a better insight into the identification of QTNs, a transethnic haplotype analysis contrasting 2 populations of African and European subjects was performed using 13 CPB2 polymorphisms. Results of the haplotype analyses suggested that 3 QTNs had independent effects and explained about 15% of the TAFI variability, consistently in the 2 populations. The lower LD observed in the African population enabled us to identify the 1583T>A SNP located in 3′UTR as one of these QTNs, whereas the -2599C>G and -2345--2344insG SNPs located in the 5′ region might be the 2 other QTNs. A phylogenetic study suggested that these 3 polymorphisms occurred before the period of migration “out of Africa.” Although this transethnic comparison contributed to better map the putative CPB2 QTNs, further studies are required to clarify the role of the promoter region.

Role of Thrombin-Activatable Fibrinolysis Inhibitor in Allergic Bronchial Asthma

Lung ◽  
2011 ◽  
Vol 190 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Atsushi Fujiwara ◽  
Osamu Taguchi ◽  
Takehiro Takagi ◽  
Corina N. D’Alessandro-Gabazza ◽  
Daniel Boveda-Ruiz ◽  
...  
Keyword(s):  
Bronchial Asthma ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor ◽  
Allergic Bronchial Asthma

Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Does not Inhibit In Vitro Thrombolysis by Pharmacological Concentrations of t-PA

2001 ◽  
Vol 85 (04) ◽  
pp. 661-666 ◽  
Author(s):  
Anna D’Aprile ◽  
Alessandra Italia ◽  
Paolo Gresele ◽  
John Morser ◽  
Nicola Semeraro ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Clot Lysis ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Experimental Conditions ◽  
Soluble Thrombomodulin ◽  
Blood Clots ◽  
Fibrinolysis Inhibitor ◽  
Vitro Model

SummaryTAFI (thrombin activatable fibrinolysis inhibitor) is a plasma procarboxypeptidase that upon activation inhibits the fibrinolytic process by removing the C-terminal lysines from partially degraded fibrin. The generation of activated TAFI (TAFIa) has been suggested to represent a mechanism of thrombus resistance to thrombolytic therapy. However, the ability of TAFI to inhibit fibrinolysis by pharmacological concentrations of t-PA has not been properly investigated. We used an in vitro model consisting of 125I-fibrin blood clots submerged in auto-logous defibrinated plasma. Upon addition of t-PA (125-5000 ng/ml) and CaCl2 (25 mM), samples were incubated at 37° C, and clot lysis was measured at intervals from the radioactivity released into solution. The role of TAFI was assessed either by neutralizing the generated TAFIa with the specific inhibitor PTI (50 g/ml) or by enhancing TAFI activation through the addition of recombinant soluble thrombomodulin (solulin, 1 μg/ml). In our clot lysis model, activation of TAFI amounted to about 20% of inducible carboxypeptidase activity. Addition of PTI, however, produced a significant increase in the extent of lysis only at concentrations of t-PA equal to or lower than 250 ng/ml. When solulin was added to the plasma surrounding the clot, about 70% of TAFI was activated within 15 min. Under these conditions, inhibition of clot lysis was very marked in samples containing 125 or 250 ng/ml of t-PA, but negligible in those containing pharmacological concentrations of the activator (1000 and 5000 ng/ml). Additional experiments suggest that loss of fibrin-dependence by elevated concentrations of t-PA may be one of the mechanisms explaining the lack of effect of TAFIa. Our data indicate that, under our experimental conditions, clot lysis by pharmacological concentrations of t-PA is not influenced by TAFIa even after maximal activation of this procarboxypeptidase.

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