Localization of ADAMTS 13 to the stellate cells of human liver

Third Department of Internal Medicine, Department of Anatomy, Nara Medical University, 840 Shijo-cho, Kashihara City, Nara, 634-8522, Japan.
Blood (Impact Factor: 10.45). 09/2005; 106(3):922-4. DOI: 10.1182/blood-2005-01-0152
Source: PubMed


Although the chromosomal localization (9q34) of the gene encoding the human form of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) and its exclusive expression in the liver have been established, the cells that produce this enzyme are yet to be determined. We investigated the expression of ADAMTS13 mRNA and protein in fresh frozen specimens obtained during liver biopsies of 8 patients with liver diseases. In situ hybridizations to localize ADAMTS13 mRNA showed positive signals exclusively in perisinusoidal cells with irregularly elongated dendritic processes extending between hepatocytes. Furthermore, ADAMTS13 was detected immunohistochemically in perisinusoidal cells, whereas no staining was observed in hepatocytes. The positive cells varied in shape from unipolar to dendritic with irregularly elongated cytoplasmic processes, features common to hepatic stellate cells (HSCs). Double-labeling experiments revealed that the ADAMTS13-positive cells also expressed alpha-smooth muscle actin, confirming that these cells were activated HSCs. These results suggest that HSCs may be major cells producing ADAMTS13 in human liver.

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    • "Human placenta and skeletal muscle synthesize a 2.4 kb ADAMTS13 mRNA.8 There are some evidences from in vivo35,36 and in vitro36,37 studies that ADAMTS13 mRNA and protein are produced in liver hepatic stellate cells. However, the contribution of hepatic stellate cells to plasma levels of ADAMTS13 remains to be determined. "
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    ABSTRACT: ADAMTS13 is a 190 kDa zinc protease encoded by a gene located on chromosome 9q34. This protease specifically hydrolyzes von Willebrand factor (VWF) multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1) repeats, a cysteine-rich domain, a spacer domain and 2 CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein) domains. ADAMTS13 cleaves a single peptide bond (Tyr1605-Met1606) in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultra-large VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form with platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs). In this review, we a) discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, b) address the recent findings concerning proteolytic processing of VWF multimers by different proteases, such as the leukocyte-derived serine and metallo-proteases and c) indicate the direction of future investigations.
    Full-text · Article · Sep 2013 · Mediterranean Journal of Hematology and Infectious Diseases
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    • "ADAMTS13 is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF) [2], while VWF is a large glycoprotein that is essential for platelet adhesion and aggregation under high shear stress conditions [3]. ADAMTS13 is mainly synthesized in the liver by stellate cells [4,5]. In addition, it is expressed by the podocytes and endothelium of the renal glomeruli, where podocyte-derived ADAMTS13 might have a local protective effect in the high shear stress glomerular microcirculation [6]. "
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    ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) is frequently associated with renal abnormalities, but there have been few reports about renal abnormalities in patients with hereditary TTP. In particular, little is known about the long-term prognosis of patients with childhood-onset congenital TTP. We report a Japanese patient with congenital TTP (Upshaw--Schulman syndrome) who was followed for 19 years after initiation of hemodialysis when he was 22 years old. At the age of 6 years, the first episode of purpura, thrombocytopenia, and proteinuria occurred without any precipitating cause. He underwent living-related donor kidney transplantation from his mother, but the graft failed after 5 months due to recurrence of TTP. Even after resection of the transplanted kidney and resumption of regular hemodialysis, TTP became refractory to infusion of fresh frozen plasma (FFP). Therefore, splenectomy was performed and his disease remained in remission for 10 years. However, TTP recurred at the age of 39 years. Plasma activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) was less than 3%, while ADAMTS13 inhibitor was not detected (< 0.5 Bethesda units/mL). The patient died suddenly after hemodialysis at the age of 41 years. Subsequent genetic analysis of this patient and his parents revealed two different heterozygous mutations of ADAMTS13, including a missense mutation in exon 26 (c.T3650C causing p.I1217T) inherited from his father and a missense mutation in exon 21 (c.G2723A causing p.C908Y) inherited from his mother. The former mutation has not been detected before in Japan, while the latter mutation is common in Japan. A retrospective review showed that serum C3 levels were consistently low while C4 levels were normal during follow-up, and C3 decreased much further during each episode of TTP. Congenital TTP was diagnosed from the clinical, biochemical, and genetic findings. Infusion of FFP controlled each thrombotic episode, but the effect was limited and of short duration. Review of the complement profile in this patient suggested that a persistently low serum C3 level might be associated with refractory TTP and a worse renal prognosis.
    Full-text · Article · Jul 2013 · BMC Nephrology
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    • "As inflammation is a complex process, the specific activity of inflammatory cytokines for the release of VWF or the suppression of ADAMTS13 synthesis may vary depending upon the in vivo conditions. ADAMTS13 is predominantly expressed in hepatic stellate cells [23] [24] and vascular endothelial cells [25]. Our study is the first to examine ADAMTS13 mRNA and protein expression levels in conditionally immortalized mouse podocyte cell line, which is a well-established podocyte cell line that express podocyte markers, such as podocin and nephrin [26] [27]. "
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    ABSTRACT: ADAMTS13 is a specific von Willebrand factor-cleaving protease. Severe deficiency of ADAMTS13 is the main cause of thrombotic thrombocytopenic purpura. ADAMTS13 is mainly synthesized and released from hepatic stellate cells and endothelial cells, but is also expressed in other cells, including kidney podocytes. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has a beneficial effect on atherosclerosis and also has anti-inflammatory and antithrombotic properties. A recent study indicates that ADAMTS13 reduces inflammatory plaque formation during early atherosclerosis in mice. In our study, we investigated the effects of simvastatin on inflammatory cytokines-induced ADAMTS13 expression in podocytes. A conditionally immortalized mouse podocyte cell line was utilized to study the expression of ADAMTS13 in podocytes. The influence of TNF-α, IL-4, IL-6 and simvastatin on ADAMTS13 was investigated. ADAMTS13 mRNA levels in podocytes were measured by using real-time PCR and protein levels were detected by Western blotting. Simvastatin significantly up-regulated the expression levels of ADAMTS13 mRNA and protein in podocytes. IL-6 decreased ADAMTS13 expression, and TNF-α had no significant effects on ADAMTS13 expression in podocytes. IL-4 reduced ADAMTS13 mRNA expression but not its protein level. Simvastatin was able also reversed the inhibitory effect of IL-6. We demonstrate that simvastatin increases the expression of ADAMTS13 in a dose-dependent manner in podocytes, which likely contributes to the antithrombotic property of statin. Different inflammatory cytokines have different effects on the levels of ADAMTS13 mRNA expression and protein within podocytes.
    Full-text · Article · Jun 2013 · Thrombosis Research
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