Low dose cadmium upregulates the expression of von Willebrand factor in endothelial cells

Wang, Xia; Fang, Dong; Wang, Fufang; Yan, Shi Fang; Chen, Jiayao; Tozawa, Hideto; Ushijima, Toshiyuki; Kapron, Carolyn M.; Wada, Youichiro; Liu, Ju

doi:10.1016/j.toxlet.2018.03.020

Cited by 17 publications

(15 citation statements)

References 50 publications

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“…Cd affects multiple organs, including liver and kidney, and the vascular system is also one of the primary targets of Cd-induced toxicity (42,43). At lower concentrations, Cd does not induce cytotoxicity in endothelial cells (7,9,44) but increases expression of vascular hemostastic factors, such as tissue factor and von Willebrand factor (45). In response to Cd, GECs produce additional CFH, which might help protect the glomerular filtration barrier from dysregulation of the complement system.…”

Section: Discussionmentioning

confidence: 99%

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Chen

Liu

et al. 2019

The Journal of Immunology

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Cadmium (Cd) is an environmental toxin that induces nephrotoxicity. Complement factor H (CFH), an inhibitor of complement activation, is involved in the pathogenesis of various renal diseases. In this study, we investigated the effects of Cd on CFH production by the kidney. In C57B6/J mice, an increased CFH level was found in renal blood and glomerular endothelial cells after Cd treatment. In vitro, Cd induces an increased CFH secretion and mRNA expression in human renal glomerular endothelial cells but not in human podocytes or human mesangial cells. Cd activates the JNK pathway and increases c-Jun and c-Fos in human renal glomerular endothelial cells. A JNK inhibitor, SP600125, specifically abolishes Cd-induced CFH production. By chromatin immunoprecipitation assay and EMSA, the −1635 AP-1 motif on human CFH promoter was identified as the binding element for c-Jun and c-Fos. In a luciferase activity assay, mutation of the AP1 site eliminates Cd-induced increase of CFH promoter activity. Thus, the −1635 AP-1 motif on the CFH promoter region mediates Cd-inducible CFH gene expression.

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Section: Discussionmentioning

confidence: 99%

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Chen

Liu

et al. 2019

The Journal of Immunology

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“…Cd increases endothelial permeability [5] and downregulation of occludin leads to elevated endothelial permeability [35]. The effects of Cd on endothelial cells are dose-dependent [1,36]. In this study we observed that expression of occludin was increased by Cd treatment in TNF-α −/− mice and in TNF-α siRNA-transfected HUVECs, suggesting that TNF-α is involved in inhibition of expression of occludin in the glomerulus.…”

Section: Discussionmentioning

confidence: 49%

Cadmium regulates von Willebrand factor and occludin expression in glomerular endothelial cells of mice in a TNF-α-dependent manner

et al. 2019

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Background: Cadmium (Cd) is an environmental pollutant that leads to nephrotoxicity. However, the mechanisms of Cd-induced glomerular injury have not been fully clarified. Von Willebrand factor (vWF) and occludin are important endothelial cell markers in renal vasculature. In this study, the effects of Cd on the vWF and occludin expression in mouse glomeruli was investigated. Objectives: The goal of this study was to analyze the expression of von Willebrand factor and occludin in glomerular endothelial cells of tumor necrosis factor-α −/− (TNF-α −/− ) mice after treatment with Cd. Material and methods: C57BL6/J wild-type (WT) mice and TNF-α −/− mice ( n = 6) were treated with Cd, and the kidney tissues were collected. The expression of von Willebrand factor and occludin was detected by using quantitative real-time PCR, immunofluorescence, and immunohistochemistry. In vitro , Human umbilical vascular endothelial cells (HUVECs) were used to examine the regulatory role of TNF-α on expression of von Willebrand factor and occludin. Results: We found that Cd significantly increases mRNA and protein expressions of von Willebrand factor and occludin in TNF-α −/− mice, but not in WT mice. In vitro , Cd significantly increased mRNA and protein expression of von Willebrand factor and occludin in HUVECs with TNF-α small interfering RNA (siRNA) transfection. Conclusions: These results suggest that TNF-α acts to balance homeostasis of glomerular endothelium after Cd treatments.

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“…Western blot was performed as previously described [27]. Primary antibodies used were rabbit anti‐vWF (1:1000, A008229) antibodies obtained from Dako (Glostrup, Denmark), and rabbit anti‐ERG (1:3000, ab133264) and rabbit anti‐GATA3 (1:1000, ab199428) antibodies obtained from Abcam (Cambridge, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Inflammation and hypoxic stimulation may increase vWF secretion [25,26]. Further, a low dose of cadmium can promote the vWF expression in ECs [27]. The vWF promoter includes several regulatory regions and specific transcription factors regulate them [28,29].…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin inhibits the expression of von Willebrand factor by downregulation of transcription factor ERG in endothelial cells

Fang

Zhao

Wang

et al. 2020

Fundamemntal Clinical Pharma

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Dihydroartemisinin (DHA), a semi‐synthetic derivative of artemisinin, has effective antitumor and anti‐inflammatory actions. von Willebrand factor (vWF), a large multifunctional glycoprotein, has a prominent function in hemostasis and is a key factor in thrombus formation. In addition, vWF has been regarded as a prospective biomarker for the diagnosis of endothelial dysfunction. In our experiment, we observed that 25 μM DHA specifically downregulated the expression of vWF mRNA and protein in human umbilical vein endothelial cells (HUVECs). Further investigations demonstrated that this DHA‐decreased vWF expression was mediated by the transcription factor ERG and not GATA3. Luciferase activity assay confirmed that DHA regulated the ERG binding with the −56 ETS‐binding motif on the human vWF promoter. Thus, the −56 ETS motif on the vWF promoter region regulates the expression of vWF gene which is induced by DHA. Taken together, we proved that DHA decreased the vWF transcription through the downregulation of ERG in HUVECs. As vWF plays a key role in vascular homeostasis, our findings suggest a new role of DHA in vascular diseases.

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Low dose cadmium upregulates the expression of von Willebrand factor in endothelial cells

Cited by 17 publications

References 50 publications

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Cadmium Induces Glomerular Endothelial Cell–Specific Expression of Complement Factor H via the −1635 AP-1 Binding Site

Cadmium regulates von Willebrand factor and occludin expression in glomerular endothelial cells of mice in a TNF-α-dependent manner

Dihydroartemisinin inhibits the expression of von Willebrand factor by downregulation of transcription factor ERG in endothelial cells

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