Methylglyoxal induces hyperpermeability of the blood–retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases

The blood—retinal barrier (BRB) is essential for the normal structural and functional integrity of the retina, whose breakdown could cause the serious vision loss. Vascular endothelial growth factor (VEGF), as a permeable factor, induces alteration of tight junction proteins to result in BRB breakdown. Herein, we demonstrated that decursin inhibits VEGF-mediated inner BRB breakdown through suppression of VEGFR-2 signaling pathway. In retinal endothelial cells, decursin inhibited VEGF-mediated hyperpermeability. Decursin prevented VEGF-mediated loss of tight junction proteins including zonula occludens-1 (ZO-1), ZO-2, and occludin in retinal endothelial cells, which was also supported by restoration of tight junction proteins in intercellular junction. In addition, decursin significantly inhibited VEGF-mediated vascular leakage from retinal vessels, which was accompanied by prevention of loss of tight junction proteins in retinal vessels. Decursin significantly suppressed VEGF-induced VEGFR-2 phosphrylation that consequently led to inhibition of extracellular signal-regulated kinase (ERK) 1/2 activation. Moreover, decursin induced no cytotoxicity to retinal endothelial cells and no retinal toxicity under therapeutic concentrations. Therefore, our results suggest that decursin prevents VEGF-mediated BRB breakdown through blocking of loss of tight junction proteins, which might be regulated by suppression of VEGFR-2 activation. As a novel inhibitor to BRB breakdown, decursin could be applied to variable retinopathies with BRB breakdown.

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Altered expression of tight junction proteins and matrix metalloproteinases in thiamine-deficient mouse brain

Neurochemistry International ◽

10.1016/j.neuint.2009.03.014 ◽

2009 ◽

Vol 55 (5) ◽

pp. 275-281 ◽

Cited By ~ 22

Author(s):

Élizabeth Beauchesne ◽

Paul Desjardins ◽

Alan S. Hazell ◽

Roger F. Butterworth

Keyword(s):

Matrix Metalloproteinases ◽

Tight Junction ◽

Mouse Brain ◽

Deficient Mouse ◽

Tight Junction Proteins ◽

Altered Expression ◽

Junction Proteins

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Reversal of West Nile virus-induced blood–brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor

Virology ◽

10.1016/j.virol.2009.10.036 ◽

2010 ◽

Vol 397 (1) ◽

pp. 130-138 ◽

Cited By ~ 80

Author(s):

Saguna Verma ◽

Mukesh Kumar ◽

Ulziijargal Gurjav ◽

Stephanie Lum ◽

Vivek R. Nerurkar

Keyword(s):

West Nile Virus ◽

Matrix Metalloproteinases ◽

Tight Junction ◽

Blood Brain Barrier ◽

Tight Junction Proteins ◽

West Nile ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Brain Barrier Disruption ◽

Junction Proteins

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Eucalyptol Blocks Diabetes-Associated Disruption of Tight Junction and Blood Retinal Barrier in Retinal Pigment Epithelial Cells and Diabetic Eyes

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_046 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 413-413

Author(s):

Dongyeon Kim ◽

Min-kyung Kang ◽

Young-Hee Kang

Keyword(s):

Epithelial Cells ◽

Tight Junction ◽

Retinal Pigment Epithelial ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Tight Junction Proteins ◽

Blood Retinal Barrier ◽

Pigment Epithelial ◽

Pigment Epithelial Cells ◽

Junction Proteins

Abstract Objectives Diabetes-associated retinal impairment has been implicated in diabetic retinopathy. Chronic hyperglycemia leads to disruption of tight junction and breakdown of blood retinal barrier. Eucalyptol is a natural organic essential oil and a monoterpenoid present in eucalyptus oil with anti-inflammatory, anti-diabetic and antioxidant properties. Methods Primary human retinal pigment epithelial cells (HRPEC) were cultured in media containing 33 mM glucose for 4 days in the presence of 1–20 μM eucalyptol. The in vivo animal study employed db/db mice orally administrated with 10 mg/kg eucalyptol. Cell lysates and mouse eye tissue extracts were prepared for Western blotting, in which antibodies of ZO-1, occludin, matrix metalloproteinase (MMP)-2 and MMP-9 were used. Results Eucalyptol enhanced epithelial induction of the tight junction proteins of ZO-1 and occludin reduced by glucose loading. Consistently, oral administration of eucalyptol to db/db mice augmented the eye tissue levels of these tight junction proteins. In addition, the induction of MMP-2 and MMP-9 involved in the degradation of extracellular matrix, was elevated by exposure of glucose to HRPEC, which was encumbered by eucalyptol in a dose-dependent manner. Conclusions These results demonstrated that eucalyptol maintained transepithelial cells integrity and blood retinal barrier in diabetic eyes. Therefore, eucalyptol may be a potent retinoprotective agent combating diabetes-associated retinal malfunction. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (2017R1A6A3A04011473).

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Endothelial Cell Barrier Impairment Induced by Glioblastomas and Transforming Growth Factor β2Involves Matrix Metalloproteinases and Tight Junction Proteins

Journal of Neuropathology & Experimental Neurology ◽

10.1097/nen.0b013e31816fd622 ◽

2008 ◽

Vol 67 (5) ◽

pp. 435-448 ◽

Cited By ~ 57

Author(s):

Hideyuki Ishihara ◽

Hisashi Kubota ◽

Raija L.P. Lindberg ◽

David Leppert ◽

Sergio M. Gloor ◽

...

Keyword(s):

Endothelial Cell ◽

Growth Factor ◽

Matrix Metalloproteinases ◽

Tight Junction ◽

Transforming Growth Factor ◽

Tight Junction Proteins ◽

Junction Proteins

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Blockade of Angiotensin II Attenuates VEGF-Mediated Blood—Retinal Barrier Breakdown in Diabetic Retinopathy

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2008.154 ◽

2008 ◽

Vol 29 (3) ◽

pp. 621-628 ◽

Cited By ~ 61

Author(s):

Jeong Hun Kim ◽

Jin Hyoung Kim ◽

Young Suk Yu ◽

Chang Sik Cho ◽

Kyu-Won Kim

Keyword(s):

Diabetic Retinopathy ◽

Angiotensin Ii ◽

Tight Junction ◽

Vascular Permeability ◽

Ace Inhibitor ◽

Ang Ii ◽

Tight Junction Proteins ◽

Blood Retinal Barrier ◽

Brb Breakdown ◽

Junction Proteins

Diabetic retinopathy (DR) is the leading cause of vision loss as a major complication of diabetes mellitus. The blood—retinal barrier (BRB) breakdown is a critical early event in the pathogenesis of DR. It has been known that the rennin-angiotensin system (RAS) is important in the progression of the DR via angiotensin II (Ang II), the effector of RAS. In this study, we showed that blockade of Ang II attenuates vascular endothelial growth factor (VEGF)-mediated BRB breakdown in DR. In streptozotocin-induced diabetes, retinal vascular permeability increased with upregulation of VEGF, where Ang II and its receptors were upregulated. Ang II induced VEGF expression in retinal endothelial cells accompanied by loss of tight junction proteins. However, the blockade of Ang II by perindopril, an angiotensin converting enzyme (ACE) inhibitor, inhibited upregulation of VEGF, and prevented the loss of tight junction proteins. Moreover, inhibition of Ang II by perindopril attenuated increased vascular permeability of diabetic retina accompanied by recovery of tight junction proteins in retinal vessels. Therefore, we suggest that the RAS involves in increased vascular permeability during early stage of DR, which is mediated by VEGF. Furthermore, the ACE inhibitor may have a therapeutic potential in the treatment of diabetic BRB breakdown.

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