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      Renal Tissue Factor Expression Is Increased in Streptozotocin-Induced Diabetic Mice


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          Background: Tissue factor (TF) is the key initiator of the coagulation cascade. Recent evidence suggests that TF plays a role in renal fibrin formation and renal failure in experimental kidney disease. We hypothesized that hyperglycemia is an important stimulus of TF expression in the kidney. Methods: Mice were injected with streptozotocin (STZ) (200 mg/kg) or with control buffer. Three or 10 weeks after injection, fibrin, thrombin and TF staining and TF activity were evaluated in the kidney. The effect of hyperglycemia on TF expression and secretion by tubular epithelial cells was measured in vitro. Results: Kidneys of STZ-treated mice showed a marked increase in thrombin staining (3.0 ± 0.5 vs. 1.2 ± 0.11) (p = 0.002) and an increase in TF clotting activity 10 weeks after STZ injection (33.9 ± 1.3 vs. 25.4 ± 1.0 s) (p < 0.0001). Increased glomerular fibrin deposition was present in 3 out of 6 diabetic mice. Tubular cells incubated with D-glucose (25 mmol/l) for 48 h displayed increased cellular TF (p = 0.05). However, soluble TF levels and TF activity in supernatant of cells incubated with D- or L-glucose were not different. Conclusions: These data suggest that hyperglycemia is a causal factor in procoagulant activity associated with diabetic nephropathy.

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          Most cited references14

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          Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease.

          The development of diabetic nephropathy in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus is still a huge clinical problem associated with increased morbidity and mortality. The mechanisms underlying the development of diabetic kidney disease are extremely complex and yet not completely understood. Among many potential pathogenic mechanisms responsible for the development of diabetic kidney disease, various growth factors have been suggested to be important players. In particular, growth hormone (GH)/insulin-like growth factors (IGFs), transforming growth factor beta (TGF-beta), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have measurable effects on the development of experimental diabetic kidney disease through complex intra-renal systems. Recent findings that these growth factors might initiate the early diabetic renal changes have provided insight into processes that might be relevant for future development of new drugs useful in the treatment of diabetic kidney disease. As will appear from the present review, enhanced understanding of the cellular mechanisms responsible for the development of diabetic kidney disease has already allowed the design of specific antagonists of pathophysiologically increased growth factors. Recent studies have shown that treating experimental diabetic models with such antagonists is followed by renoprotection.
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            Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain.

            Tissue factor (TF) is the physiological activator of the coagulation cascade that plays pathophysiological roles in metastasis, angiogenesis, and inflammation. Downstream in coagulation, thrombin is the central protease that signals through G protein-coupled, protease-activated receptors (PARs). However, the TF-VIIa-Xa complex upstream in coagulation also activates PAR1 and 2. Here, we address the question of whether signaling of the TF initiation complex is a relevant pathway that leads to TF cytoplasmic domain phosphorylation. In heterologous expression systems and primary endothelial cells, we demonstrate that the ternary TF-VIIa-Xa complex induces TF phosphorylation specifically by activating PAR2 but not through PAR1 signaling. In addition, TF cytoplasmic domain phosphorylation is induced only by TF-dependent signaling but not by other coagulation factors in endothelial cells. Phosphorylation of the Pro-directed kinase target site Ser258 is dependent on prior phosphorylation of Ser253 by protein kinase C (PKC) alpha. TF phosphorylation is somewhat delayed and coincides with sustained PKCalpha activation downstream of PAR2 but not PAR1 signaling. Phosphatidylcholine-dependent phospholipase C is the major pathway that leads to prolonged PKCalpha recruitment downstream of PAR2. Thus, PAR2 signaling specifically phosphorylates TF in a receptor cross-talk that distinguishes upstream from downstream coagulation protease signaling.
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              Regulation of tissue factor gene expression in obesity.

              Altered expression of proteins of the fibrinolytic and coagulation cascades in obesity may contribute to the cardiovascular risk associated with this condition. In spite of this, the zymogenic nature of some of the molecules and the presence of variable amounts of activators, inhibitors, and cofactors that alter their activity have made it difficult to accurately monitor changes in the activities of these proteins in tissues where they are synthesized. Thus, as a first approach to determine whether tissue factor (TF) expression is altered in obesity, this study examined changes in TF mRNA in various tissues from lean and obese (ob/ob and db/db) mice. TF gene expression was elevated in the brain, lung, kidney, heart, liver, and adipose tissues of both ob/ob and db/db mice compared with their lean counterparts. In situ hybridization analysis indicated that TF mRNA was elevated in bronchial epithelial cells in the lung, in myocytes in the heart, and in adventitial cells lining the arteries including the aortic wall. Obesity is associated with insulin resistance and hyperinsulinemia, and administration of insulin to lean mice induced TF mRNA in the kidney, brain, lung, and adipose tissue. These observations suggest that the hyperinsulinemia associated with insulin-resistant states, such as obesity and noninsulin-dependent diabetes mellitus, may induce local TF gene expression in multiple tissues. The elevated TF may contribute to the increased risk of atherothrombotic disease that accompanies these conditions.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                November 2005
                01 July 2005
                : 101
                : 3
                : e86-e94
                aLaboratory for Experimental Internal Medicine and bDepartment of Pathology, AMC, Amsterdam; cDepartment of Internal Medicine and Cardiovascular Research Institute Maastricht, Academic Hospital, and University of Maastricht, Maastricht, The Netherlands
                86646 Nephron Exp Nephrol 2005;101:e86–e94
                © 2005 S. Karger AG, Basel

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                : 25 February 2005
                : 04 April 2005
                Page count
                Figures: 6, Tables: 1, References: 31, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86646
                Self URI (text/html): https://www.karger.com/Article/FullText/86646
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Streptozotocin-induced diabetic mice,Nephropathy,Tissue factor,Diabetes


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