Regulation of tight junctions and loss of barrier function in pathophysiology

Harhaj, Nicole S.; Antonetti, David A.

doi:10.1016/j.biocel.2003.08.007

Cited by 480 publications

(394 citation statements)

References 230 publications

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“…55 It is a member of a group of growth factors and hormones that alter vascular permeability by regulating tight junctions. 33 In the eye, excessive VEGF has been implicated as a detrimental factor causing neovascularization and vascular leakage in age-related macular degeneration 34 and in proliferative retinopathies. 56 VEGF is not only up-regulated in response to hypoxia and nonperfusion, but may also be an underlying cause of them.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Furthermore, it was suggested that VEGF may alter vascular permeability by regulating tight junctions. 33 Therefore, we investigated whether the vascular differences we observed between retinas of Atm Ϫ/Ϫ and WT mice may be related to changes in VEGF expression levels. Analysis of retinal mRNA levels revealed a significant increase of 40% in VEGF in the eyes of Atm Ϫ/Ϫ mice relative to WT controls ( Figure 2A).…”

Section: Increased Expression Of Vegf In Atm ϫ/ϫ Retinasmentioning

confidence: 99%

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A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

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Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atmdeficient mice (Atm ؊/؊ ). At 2 months of age, angiography revealed faint retinal vasculature in Atm ؊/؊ animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm ؊/؊ retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Some brain disorders may have a vascular origin, 1,2 and vascular diseases can be directly linked to neuronal and synaptic dysfunction through changes in the blood flow, increase in blood-brain barrier permeability, and in nutrient supply. 3 A healthy brain relies on the proper function and communication of all cells comprising the neurovascular unit: neurons, astrocytes, brain endothelium, and vascular smooth muscle cells. 4 Impaired genomic stability interferes with cellular homeostasis and poses a constant threat to cellular viability. 5 The cell combats this threat by activating the DNA damage response (DDR), a complex signaling network that detects the DNA lesions, promotes their repair, and temporarily modulates cellular metabolism while the damage is being repaired. 6 The DDR is vigorously activated by DNA double-strand breaks (DSBs), a particularly cytotoxic DNA lesion induced by ionizing radiation, radiomimetic chemicals, and oxygen radicals. 7,8 The DNA damage response is a hierarchical process executed by sensor/mediator proteins that accumulate at DSB sites and by protein kinases that serve as transducers of the DNA damage alarm to numerous downstream effectors. 6 The primary transducer of the cellular response to DSBs is the protein kinase ATM, which phosphorylates many key players in the various branches of the DDR. 9 Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene that encodes the ATM protein. 10 A-T is characterized by progressive neurodegeneration affecting mainly the cerebellum, which develops into severe neuromotor dysfunction;

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Section: Discussionmentioning

confidence: 99%

Section: Increased Expression Of Vegf In Atm ϫ/ϫ Retinasmentioning

confidence: 99%

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Raz-Prag

Galron

Segev-Amzaleg

et al. 2011

The American Journal of Pathology

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“…In porcine intestinal epithelial cells (IPEC-1) and -J2 cells, the treatment with 2 mg DON/ml led to disintegrated TJP1 structure and the total amount of TJP1 moderately decreased, which was measured with the Western blot analysis (Diesing et al, 2011). It was reported that TJP1 interacts with CLDN3 (fc: 11.637, DON1/5; Harhaj and Antonetti, 2004). Pinton et al (2009) have shown a decreased CLDN3 protein amount in IPEC-1 after the treatment with DON for 48 h with a parallel decrease of TEER.…”

Section: Translation Initiationmentioning

confidence: 99%

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Dietrich

Neuenschwander

Bucher

et al. 2012

Animal

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The effects of mycotoxins in the production of animal feed were investigated using broiler chickens. For the feeding trial, naturally Fusarium mycotoxin-contaminated wheat was used, which mainly contained deoxynivalenol (DON). The main effects of DON are reduction of the feed intake and reduced weight gain of broilers. At the molecular level, DON binds to the 60 S ribosomal subunit and subsequently inhibits protein synthesis at the translational level. However, little is known about other effects of DON, for example, at the transcriptional level. Therefore, a microarray analysis was performed, which allows the investigation of thousands of transcripts in one experiment. In the experiment, 20 broilers were separated into four groups of five broilers each at day 1 after hatching. The diets consisted of a control diet and three diets with calculated, moderate concentrations of 1.0, 2.5 and 5.0 mg DON/kg feed, which was attained by exchanging uncontaminated wheat with naturally mycotoxin-contaminated wheat up to the intended DON concentration. The broilers were held at standard conditions for 23 days. Three microarrays were used per group to determine the significant alterations of the gene expression in the liver (P , 0.05), and qPCR was performed on the liver and the jejunum to verify the results. No significant difference in BW, feed intake or feed conversion rate was observed. The nutrient uptake into the hepatic and jejunal cells seemed to be influenced by genes: SLC2A5 (fc: 21.54, DON2.5), which facilitates glucose and fructose transport and SLC7A10 (fc: 11.49, DON5), a transporter of D-serine and other neutral amino acids. In the jejunum, the palmitate transport might be altered by SLC27A4 (fc: 21.87, DON5) and monocarboxylates uptake by SLC16A1 (fc: 21.47, DON5). The alterations of the SLC gene expression may explain the reduced weight gain of broilers chronically exposed to DON-contaminated wheat. The decreased expressions of EIF2AK3 (fc: 21.29, DON2.5/5) and DNAJC3 (fc: 21.44, DON2.5) seem to be related to the translation inhibition. The binding of DON to the 60 S ribosomal subunit and the subsequent translation inhibition might be counterbalanced by the downregulation of EIF2AK3 and DNAJC3. The genes PARP1, MPG, EME1, XPAC, RIF1 and CHAF1B are mainly related to single-strand DNA modifications and showed an increased expression in the group with 5 mg DON/kg feed. The results indicate that significantly altered gene expression was already occurring at 2.5 mg DON/kg feed.

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“…Like most solid tumors, gliomas express and secrete vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) that induces proliferation and migration of neighboring endothelial cells [32][33][34][35][36]. Remodeling of the BBB vasculature by VEGF disrupts the formation of tight junctions, increases vascular permeability (VP), and results in a disordered vasculature characteristic of tumor-induced angiogenesis [34,[37][38][39]. Our previous studies have demonstrated that the non-receptor tyrosine kinase, Src, is essential for the maintenance of the BBB [40].…”

Section: Introductionmentioning

confidence: 99%

Reduced Glioma Infiltration in Src-deficient Mice

et al. 2006

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SummaryMalignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant factor in tumor recurrence following surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated vascular permeability (VP) has been associated with the progression of glioma tumor growth and infiltration into surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src +/+ or src +/− ), the VP response is blocked in src −/− mice that demonstrate a 'leakage-resistant phenotype' in the brain. We used the Src-deficient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src −/− mice, the infiltrating component of glioma growth was reduced in src −/− mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect of a Src-mediated VP defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src −/− mice mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.

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Regulation of tight junctions and loss of barrier function in pathophysiology

Cited by 480 publications

References 230 publications

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia

Fusarium mycotoxin-contaminated wheat containing deoxynivalenol alters the gene expression in the liver and the jejunum of broilers

Reduced Glioma Infiltration in Src-deficient Mice

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