Actin cytoskeleton-dependent pathways for ADMA-induced NF-&amp;kappa;B activation and TGF-&amp;beta; high expression in human renal glomerular endothelial cells

Wang, Liyan; Zhang, Dongliang; Zheng, Junfang; Feng, Yiduo; Zhang, Yu; Liu, Wenhu

doi:10.1093/abbs/gms077

Cited by 18 publications

(18 citation statements)

References 24 publications

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“…The concentrations of ADMA used in this study were similar to those previously reported [21,29], and were much higher than those in the plasma of patients. For the in vitro experiments, the duration was limited; therefore, a low dose of ADMA (5 mM), similar to that observed in uremia patients, failed to activate the NF-kB (data not shown).…”

Section: Discussionsupporting

confidence: 89%

Disruption of asymmetric dimethylarginine-induced RelA/P65 association with actin in endothelial cells

Wei

Zhang

Wang

et al. 2013

ABBS

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Asymmetric dimethylarginine (ADMA) activates nuclear factor (NF)-kB in endothelial cells, while actin-stabilizing or -destabilizing drugs prevent ADMA-induced activation of NF-kB. Here we investigated how actin-targeting drugs regulated ADMA-induced NF-kB activation in endothelial cells. Human umbilical vein endothelial cells were treated with ADMA for 24 h in the absence and presence of cytochalasin D or jasplakinolide. Expression levels of proteins and genes were measured by immunoblotting and reversetranscription polymerase chain reaction, respectively. Chromatin immunoprecipitation was used to detect the binding of NF-kB to the vascular cell adhesion molecule 1 (VCAM-1) promoter. The association of actin with RelA/ P65 was detected by immunoprecipitation. It was demonstrated that ADMA induced IkBa degradation, increased nuclear RelA/P65 translocation, and promoted the binding of NF-kB to the VCAM-1 promoter. Consequently, this increased the expression of VCAM-1. In parallel studies, actin-stabilizing and -destabilizing drugs decreased ADMAinduced RelA/P65 nuclear translocation, interfered with NF-kB binding to the VCAM-1 promoter and prevented the expression of VCAM-1. This was independent of total RelA/ P65 levels and ADMA-induced IkBa degradation. Most importantly, the association of RelA/P65 with actin was increased after stimulation with ADMA, and impaired after treatment with actin-targeting drugs. In brief, actinstabilizing or -destabilizing drugs interfere with the ADMAinduced association of RelA/P65 with actin, and consequently disrupt NF-kB activation.

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Section: Discussionsupporting

confidence: 89%

Disruption of asymmetric dimethylarginine-induced RelA/P65 association with actin in endothelial cells

Wei

Zhang

Wang

et al. 2013

ABBS

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“…25,26,75,76,80,81 At the same time, it has been reported that NF-kB activation induces TGF-b production. [82][83][84] Thus, there is a potential positive feedback mechanism between TGF-b production and NF-kB activation that enhances the fibrotic process. (vi) Furthermore, we used RT-qPCR and protein detection by western blot to demonstrate that H 2 O 2 induces the expression and secretion of TGF-b1 and TGF-b2, and it has been clearly demonstrated that TGF-b1 and TGF-b2 induce the conversion of ECs into myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

120

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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“…These findings indicate that TGF-b is a very important inducer of PRMT1 in inflammation. Although there is no direct evidence to prove the relationship between TGF-b and PRMT1, a study on renal fibrosis was found that ADMA, as an endogenous endothelial NO synthase and inducible NO synthase competitive inhibitor (17,18), can reduce the NO concentration in serum in asthmatic animals (7); furthermore, ADMA is also involved in proline metabolism, which may play an important role in the pulmonary remodeling process through raising collagen synthesis (19). In our study, the supplementation of TGF-b to basic medium increased the expression of PRMT1 in fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation

Sun

Liu

Roth

et al. 2015

The Journal of Immunology

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Protein arginine methyltransferase (PRMT)1, methylating both histones and key cellular proteins, has emerged as a key regulator of various cellular processes. This study aimed to identify the mechanism that regulates PRMT1 in chronic Ag-induced pulmonary inflammation (AIPI) in the E3 rat asthma model. E3 rats were challenged with OVA for 1 or 8 wk to induce acute or chronic AIPI. Expression of mRNAs was detected by real-time quantitative PCR. PRMT1, TGF-β, COX2, and vascular endothelial growth factor protein expression in lung tissues was determined by immunohistochemistry staining and Western blotting. In the in vitro study, IL-4–stimulated lung epithelial cell (A549) medium (ISEM) with or without anti–TGF-β Ab was applied to human fibroblasts from lung (HFL1). The proliferation of HFL1 was determined by MTT. AMI-1 (pan-PRMT inhibitor) was administered intranasally to chronic AIPI rats to determine PRMT effects on asthmatic parameters. In lung tissue sections, PRMT1 expression was significantly upregulated, mainly in epithelial cells, in acute AIPI lungs, whereas it was significantly upregulated mainly in fibroblasts in chronic AIPI lungs. The in vitro study revealed that ISEM elevates PRMT1, COX2, and vascular endothelial growth factor expressions, and it promoted fibroblast proliferation. The application of anti–TGF-β Ab suppressed COX2 upregulation by ISEM. AMI-1 inhibited the expression of COX2 in TGF-β–stimulated cells. In the in vivo experiment, AMI-1 administered to AIPI rats reduced COX2 production and humoral immune response, and it abrogated mucus secretion and collagen generation. These findings suggested that TGF-β–induced PRMT1 expression participates in fibroblast proliferation and chronic airway inflammation in AIPI.

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Actin cytoskeleton-dependent pathways for ADMA-induced NF-κB activation and TGF-β high expression in human renal glomerular endothelial cells

Cited by 18 publications

References 24 publications

Disruption of asymmetric dimethylarginine-induced RelA/P65 association with actin in endothelial cells

Disruption of asymmetric dimethylarginine-induced RelA/P65 association with actin in endothelial cells

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

PRMT1 Upregulated by Epithelial Proinflammatory Cytokines Participates in COX2 Expression in Fibroblasts and Chronic Antigen-Induced Pulmonary Inflammation

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